Administration of an anti-obesity compound to individuals with renal impairment

ABSTRACT

The present disclosure relates to methods for weight management in an individual in need thereof by determining the level of renal sufficiency of the individual and prescribing or administering a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to the individual, provided that the individual has a level of renal sufficiency selected from the group consisting of: no renal impairment, mild renal impairment, and moderate renal impairment. In addition, the disclosure relates to a method for selecting an individual for treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof from a plurality of individuals in need of weight management by determining the level of renal sufficiency of the individual and selecting the individual for treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof if the individual has a level of renal sufficiency selected from the group consisting of: no renal impairment, mild renal impairment, and moderate renal impairment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/671,151 filed Mar. 27, 2015, now abandoned, which is a continuationof U.S. patent application Ser. No. 13/511,639 filed May 23, 2012, nowU.S. Pat. No. 8,999,970, which is a 35 USC 371 of InternationalApplication No. PCT/US2011/049936 filed Aug. 31, 2011, and claimsbenefit of U.S. Provisional Application No. 61/403,149 filed Sep. 10,2010 and 61/402,628 filed Sep. 1, 2010.

Provided herein are methods useful in the prophylaxis or treatment ofobesity in different populations of individuals, including those withrenal impairment. In the methods provided herein, lorcaserin isprescribed or administered to an individual in need of treatment if theydo not have severe renal impairment or end stage renal disease (ESRD).

CONCURRENTLY FILED APPLICATIONS RELATED TO(R)-8-CHLORO-1-METHYL-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE

The following United States provisional applications are related to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine: 61/402,578;61/403,143; 61/402,580; 61/402,628; 61/403,149; 61/402,589; 61/402,611;61/402,565; 61/403,185; each of which is incorporated herein byreference in its entirety.

The following applications are related to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and have thesame filing date as the subject application: a PCT application whichclaims priority to U.S. provisional applications 61/402,578 and61/403,1439; a PCT application which claims priority to U.S. provisionalapplication 61/402,580; a PCT application which claims priority to U.S.provisional application 61/402,589; a PCT application which claimspriority to U.S. provisional application 61/402,611; and a PCTapplication which claims priority to U.S. provisional applications61/402,565 and 61/403,185; each of which is incorporated herein byreference in its entirety.

BACKGROUND

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas type II diabetes, hypertension, stroke, cancer and gallbladderdisease.

Obesity is now a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in numbers ofobese people is due largely to the increasing preference for high fatcontent foods but also the decrease in activity in most people's lives.Currently about 30% of the population of the USA is now consideredobese.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see table below).

CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION<18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9Obesity (Class I) 35.0-39.9 Obesity (Class II) >40   Extreme Obesity(Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that are independent of other risk factors. The most commondiseases associated with obesity are cardiovascular disease(particularly hypertension), diabetes (obesity aggravates thedevelopment of diabetes), gall bladder disease (particularly cancer) anddiseases of reproduction. The strength of the link between obesity andspecific conditions varies. One of the strongest is the link with type 2diabetes. Excess body fat underlies 64% of cases of diabetes in men and77% of cases in women (Seidell, Semin Vasc Med 5:3-14 (2005)). Researchhas shown that even a modest reduction in body weight can correspond toa significant reduction in the risk of developing coronary heartdisease.

There are problems however with the BMI definition in that it does nottake into account the proportion of body mass that is muscle in relationto fat (adipose tissue). To account for this, obesity can also bedefined on the basis of body fat content: greater than 25% in males andgreater than 30% in females.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplications induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents would decrease by 35%. The incidence of coronarydiseases is doubled in subjects less than 50 years of age who are 30%overweight. The diabetes patient faces a 30% reduced lifespan. After age45, people with diabetes are about three times more likely than peoplewithout diabetes to have significant heart disease and up to five timesmore likely to have a stroke. These findings emphasize theinter-relations between risks factors for diabetes and coronary heartdisease and the potential value of an integrated approach to theprevention of these conditions based on the prevention of obesity(Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

The first line of treatment is to offer diet and life style advice topatients such as reducing the fat content of their diet and increasingtheir physical activity. However, many patients find this difficult andneed additional help from drug therapy to maintain results from theseefforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity because of a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of patients led to itswithdrawal by the FDA in 1998.

In addition, two drugs have been launched in the USA and Europe:Orlistat (Xenical™), a drug that prevents absorption of fat by theinhibition of pancreatic lipase, and Sibutramine (Reductil™), a5-HT/noradrenaline re-uptake inhibitor. However, side effects associatedwith these products may limit their long-term utility. Treatment withXenical™ is reported to induce gastrointestinal distress in somepatients, while Sibutramine has been associated with raised bloodpressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in physical and in psychiatric disorders.5-HT has been implicated in the regulation of feeding behavior. 5-HT isbelieved to work by inducing a feeling of satiety, such that a subjectwith enhanced 5-HT stops eating earlier and fewer calories are consumed.It has been shown that a stimulatory action of 5-HT on the 5-HT_(2C)receptor plays an important role in the control of eating and in theanti-obesity effect of d-fenfluramine. As the 5-HT_(2C) receptor isexpressed in high density in the brain (notably in the limbicstructures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVNand DMH, and predominantly in the choroid plexus) and is expressed inlow density or is absent in peripheral tissues, a selective 5-HT_(2C)receptor agonist can be a more effective and safe anti-obesity agent.Also, 5-HT_(2C) knockout mice are overweight with cognitive impairmentand susceptibility to seizure.

It is believed that the 5-HT_(2C) receptor may play a role in obsessivecompulsive disorder, some forms of depression, and epilepsy.Accordingly, agonists can have anti-panic properties, and propertiesuseful for the treatment of sexual dysfunction.

In sum, the 5-HT_(2C) receptor is a receptor target for the treatment ofobesity and psychiatric disorders, and it can be seen that there is aneed for selective 5-HT_(2C) agonists which safely decrease food intakeand body weight.

Compounds and formulations presented herein can comprise the selective5-HT_(2C)-receptor agonist(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1),and are useful for, inter alia, weight management, including weight lossand the maintenance of weight loss. Compound 1 is disclosed in PCTpatent publication WO2003/086303, which is incorporated herein byreference in its entirety.

Various synthetic routes to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its relatedsalts, enantiomers, crystalline forms, and intermediates, have beenreported in WO 2005/019179, WO2006/069363, WO2007/120517, WO2008/070111,and WO2009/111004 each of which is incorporated herein by reference inits entirety.

Combinations of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with otheragents, including without limitation, phentermine, and uses of suchcombinations in therapy are described in WO2006/071740, which isincorporated herein by reference in its entirety.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(lorcaserin hydrochloride) is an agonist of the 5-HT_(2C) receptor andshows effectiveness at reducing obesity in animal models and humans. InDecember 2009, Arena Pharmaceuticals submitted a New Drug Application,or NDA, for lorcascrin to the FDA. The NDA submission is based on anextensive data package from lorcaserin's clinical development programthat includes 18 clinical trials totaling 8,576 patients. The pivotalphase 3 clinical trial program evaluated nearly 7,200 patients treatedfor up to two years, and showed that lorcaserin consistently producedsignificant weight loss with excellent tolerability. About two-thirds ofpatients achieved at least 5% weight loss and over one-third achieved atleast 10% weight loss. On average, patients lost 17 to 18 pounds orabout 8% of their weight. Secondary endpoints, including bodycomposition, lipids, cardiovascular risk factors and glycemic parametersimproved compared to placebo. In addition, heart rate and blood pressurewent down. Lorcaserin did not increase the risk of cardiac valvulopathy.Lorcaserin improved quality of life, and there was no signal fordepression or suicidal ideation. The only adverse event that exceededthe placebo rate by 5% was generally mild or moderate, transientheadache. Based on a normal BMI of 25, patients in the first phase 3trial lost about one-third of their excess body weight. The averageweight loss was 35 pounds or 16% of body weight for the top quartile ofpatients in the second phase 3 trial.

Applicants have disclosed herein the interaction of renal sufficiencywith the pharmacokinetics, tolerability and safety of lorcaserin in aformal pharmacokinetic study in subjects with renal impairment and inthe populations studied in phase 2 and phase 3 clinical studies.

Renal sufficiency can be measured by several methods. For example,measuring creatinine clearance in an individual using serum creatininelevel and a timed urine collection gives an estimate of glomerularfiltration rate, which is the unit measure of kidney function. Anindividual can be classified as having normal renal function if thecreatinine clearance rate is greater than 80 mL/min. Mild renalimpairment is defined as a creatinine clearance rate of 51-80 mL/min,moderate renal impairment is 31-50 mL/min, and severe renal impairmentis less than or equal to 30 mL/min. A further level of renal impairmentis an individual who requires hemodialysis (end stage renal disease).

There exists a need for safely treating individuals who are in need oftreatment with lorcaserin, including individuals with renal impairment.The present disclosure satisfies this need and provides relatedadvantages as well.

SUMMARY

(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(lorcaserin) is eliminated primarily by liver metabolism, whereas theresulting major metabolites M1 (lorcaserin sulfamate) and M5(N-carbamoyl glucuronide of lorcaserin) are eliminated by urinaryexcretion.

Applicants have found that the maximum concentration (C_(max)) of the M1and M5 metabolites of lorcaserin can be quite variable in individualswith severe renal impairment or ESRD. For example, four hours afteradministration of lorcaserin, the mean plasma concentration of the M1metabolite in a group of eight individuals with severe renal impairmentwas 99.5 ng/mL (Table 13 for day 1, 4 hours). However, one of the eightindividuals with severe renal impairment, subject 3285-009, had a meanplasma concentration of 542 ng/mL of M1 four hours after administrationof lorcaserin (Table 13 for subject 3285-009 at day 1, 4 hours). Thus,this individual had a level of M1 that was five times the mean level forthe severe renal impairment group.

To better assess the potential implications of M1 and M5 levels inpatients, steady state exposures (i.e. the state of equilibrium obtainedat the end of a certain number of dosings) following lorcaserin 10 mgtwice daily (BID) dosing were modeled using simulations andnoncompartmental analysis based on data from pharmacokinetic studieswith once daily (QD) dosing. The modeled steady state C_(max) formetabolite M1 in the severe renal impairment group was 1090 ng/mL (Table8); however, given the individual variability seen with this metabolite,it is possible that a particular individual with severe renal impairmentwould reach a level of five times this amount (i.e., over 5000 ng/mL)according to the model. Applicants are not aware of any toxicityassociated with metabolite M1 or M5; however, some of the levels ofthese metabolites observed in the severe renal impairment group arehigher than those levels that have been analyzed in human clinicaltrials. In addition, a level of over 5000 ng/mL of M1 in a severe renalimpairment individual is approximately the C_(max) in monkeys at the noobservable adverse event level (NOAEL) dose of lorcascrin (Table 9 M1C_(max) is 5.01 t 2.16 μg/mL for monkeys at the 2 mg/kg dose oflorcaserin). Therefore, there is no margin between exposure levels atthe NOAEL dose and projected exposure levels in some individuals withsevere renal impairment. Since some of the levels of M1 observed in thesevere renal impairment group are higher than those levels that havebeen analyzed in human clinical trials, lorcaserin is contraindicatedfor individuals with severe renal impairment and for individuals withESRD given the currently available data.

It should be noted that in the study results to date (as of the filingof the first priority document of the subject application), theincidence of adverse events due to lorcaserin was not related to theseverity of renal impairment of the individual (Example 6). However,given possible widespread use of lorcaserin in humans, in an abundanceof caution given the currently available data, lorcascrin iscontraindicated for individuals with severe renal impairment and forindividuals with ESRD.

In a first aspect, a method for weight management in an individual inneed thereof, comprising a) determining the level of renal sufficiencyof the individual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a second aspect, a method for weight management in an individual inneed thereof, comprising: a) determining the level of renal sufficiencyof the individual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD) is disclosed.

In a third aspect, a method for weight management in an individual inneed thereof, comprising: a) determining the level of renal sufficiencyof the individual, and b) prescribing or administering a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a fourth aspect, a method for weight management in an individual inneed thereof, comprising: a) determining an approximate serum creatinineconcentration for the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed.

In a fifth aspect, a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a sixth aspect, a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a seventh aspect, a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation isdisclosed.

In an eighth aspect, a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a ninth aspect, a method for reducing the risk of an adverse event inan individual in need of weight management, comprising: a) determiningthe level of renal sufficiency of the individual, and b) prescribing oradministering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a tenth aspect, a method for reducing the risk of an adverse event inan individual in need of weight management, comprising: a) determiningan approximate serum creatinine concentration for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed.

In an eleventh aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment is disclosed.

In a twelfth aspect, a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a thirteenth aspect, a compound for use in a method of weightmanagement in an individual, said method comprising prescribing oradministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a fourteenth aspect, a compound for use in a method of weightmanagement in an individual, said method comprising prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed

In a fifteenth aspect, a compound for use in a method of weightmanagement in an individual, said method comprising determining thelevel of renal sufficiency of said individual and prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual has alevel of renal sufficiency selected from the group consisting of: norenal impairment, mild renal impairment, moderate renal impairment,severe renal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a sixteenth aspect, a low dosage formulation of a compound for use ina method of weight management in an individual, said method comprisingprescribing or administering said low dosage formulation of the compoundto said individual, wherein said individual has previously beendetermined to have renal impairment; wherein said compound isR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a seventeenth aspect, a low dosage formulation of a compound for usein a method of weight management in an individual, wherein said lowdosage reduces or prevents a toxic event in said individual to saidcompound, wherein said individual has previously been determined to haverenal impairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In the first through seventeenth aspects, the following embodiments, forexample and without limitation, are envisioned. In some embodiments,said weight management comprises weight loss. In some embodiments, saidweight management comprises maintenance of weight loss. In someembodiments, said weight management further comprises prescribing oradministering a reduced-calorie diet. In some embodiments, said weightmanagement further comprises prescribing or administering a program ofregular exercise. In some embodiments, said weight management furthercomprises prescribing or administering both a reduced-calorie diet and aprogram of regular exercise. In some embodiments, said individual is anindividual with an initial body mass index ≧30 kg/m². In someembodiments, said individual is an individual with an initial body massindex ≧27 kg/m² in the presence of at least one weight related comorbidcondition. In some embodiments, said weight related comorbid conditionis selected from the group consisting of: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea. In someembodiments, the methods of the first through seventeenth aspectsfurther comprise prescribing or administering phentermine to saidindividual. In some embodiments, the Cockcroft-Gault equation is used todetermine the level of renal sufficiency of the individual. In someembodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in some embodiments the individual's actualbody weight is used in the Cockcroft-Gault equation. In someembodiments, the individual's serum creatinine concentration is used todetermine the level of renal sufficiency of the individual.

In an eighteenth aspect, a method for decreasing food intake in anindividual in need thereof, comprising a) determining the level of renalsufficiency of the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a nineteenth aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD) is disclosed.

In a twentieth aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a twenty first aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a twenty second aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a twenty third aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a twenty fourth aspect, a method for decreasing food intake in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation isdisclosed.

In an twenty fifth aspect, a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a twenty sixth aspect, a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a twenty seventh aspect, a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a twenty eighth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprising:a) determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment is disclosed.

In a twenty ninth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprising:a) determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a thirtieth aspect, a compound for use in a method of decreasing foodintake in an individual, said method comprising prescribing oradministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a thirty first aspect, a compound for use in a method of decreasingfood intake in an individual, said method comprising prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a thirty second aspect, a compound for use in a method of decreasingfood intake in an individual, said method comprising determining thelevel of renal sufficiency of said individual and prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual has alevel of renal sufficiency selected from the group consisting of: norenal impairment, mild renal impairment, moderate renal impairment,severe renal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a thirty third aspect, a low dosage formulation of a compound for usein a method of decreasing food intake in an individual, said methodcomprising prescribing or administering said low dosage formulation ofthe compound to said individual, wherein said individual has previouslybeen determined to have renal impairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a thirty fourth aspect, a low dosage formulation of a compound foruse in decreasing food intake in an individual, wherein said low dosagereduces or prevents a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In the eighteenth through thirty fourth aspects, the followingembodiments, for example and without limitation, are envisioned. In someembodiments, said individual in need of decreasing food intake is anindividual with an initial body mass index ≧30 kg/m². In someembodiments, said individual in need of decreasing food intake is anindividual with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition. In some embodiments,said weight related comorbid condition is selected from the groupconsisting of: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea. In some embodiments, the methods ofthe eighteenth through thirty forth aspects further comprise prescribingor administering phentermine to said individual. In some embodiments,the Cockcroft-Gault equation is used to determine the level of renalsufficiency of the individual. In some embodiments, the individual'sideal body weight is used in the Cockcroft-Gault equation and in someembodiments the individual's actual body weight is used in theCockcroft-Gault equation. In some embodiments, the individual's serumcreatinine concentration is used to determine the level of renalsufficiency of the individual.

In a thirty fifth aspect, a method for inducing satiety in an individualin need thereof, comprising a) determining the level of renalsufficiency of the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a thirty sixth aspect, a method for inducing satiety in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD) is disclosed.

In a thirty seventh aspect, a method for inducing satiety in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a thirty eighth aspect, a method for inducing satiety in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a thirty ninth aspect, a method for inducing satiety in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a fortieth aspect, a method for inducing satiety in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a forty first aspect, a method for inducing satiety in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation isdisclosed.

In an forty second aspect, a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a forty third aspect, a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a forty fourth aspect, a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a forty fifth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment is disclosed.

In a forty sixth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1 methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a forty seventh aspect, a compound for use in a method of inducingsatiety in an individual, said method comprising prescribing oradministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed

In a forty eighth aspect, a compound for use in a method of inducingsatiety in an individual, said method comprising prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a forty ninth aspect, a compound for use in a method of inducingsatiety in an individual, said method comprising determining the levelof renal sufficiency of said individual and prescribing or administeringsaid compound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, moderate renal impairment, severerenal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a fiftieth aspect, a low dosage formulation of a compound for use ina method of inducing satiety in an individual, said method comprisingprescribing or administering said low dosage formulation of the compoundto said individual, wherein said individual has previously beendetermined to have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a fifty first aspect, a low dosage formulation of a compound for usein a method of inducing satiety in an individual, wherein said lowdosage reduces or prevents a toxic event in said individual to saidcompound, wherein said individual has previously been determined to haverenal impairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In the thirty fifth through fifty first aspects, the followingembodiments, for example and without limitation, are envisioned. In someembodiments, said individual in need of inducing satiety is anindividual with an initial body mass index ≧30 kg/m². In someembodiments, said individual in need of inducing satiety is anindividual with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition. In some embodiments,said weight related comorbid condition is selected from the groupconsisting of: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea. In some embodiments, the methods ofthe thirty fifth through fifty first aspects further compriseprescribing or administering phentermine to said individual. In someembodiments, the Cockcroft-Gault equation is used to determine the levelof renal sufficiency of the individual. In some embodiments, theindividual's ideal body weight is used in the Cockcroft-Gault equationand in some embodiments the individual's actual body weight is used inthe Cockcroft-Gault equation. In some embodiments, the individual'sserum creatinine concentration is used to determine the level of renalsufficiency of the individual.

In a fifty second aspect, a method for treatment of obesity in anindividual in need thereof, comprising a) determining the level of renalsufficiency of the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a fifty third aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD) is disclosed.

In a fifty fourth aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a fifty fifth aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a fifty sixth aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a fifty seventh aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a fifty eighth aspect, a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation isdisclosed.

In an fifty ninth aspect, a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a sixtieth aspect, a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a sixty first aspect, a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In an sixty second aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment is disclosed.

In a sixty third aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment for obesity, comprising:a) determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a sixty fourth aspect, a compound for use in a method for treatmentof obesity in an individual, said method comprising prescribing oradministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a sixty fifth aspect, a compound for use in a method for treatment ofobesity in an individual, said method comprising prescribing andadministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a sixty sixth aspect, a compound for use in a method for treatment ofobesity in an individual, said method comprising determining the levelof renal sufficiency of said individual and prescribing or administeringsaid compound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, moderate renal impairment, severerenal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a sixty seventh aspect, a low dosage formulation of a compound foruse in a method for treatment of obesity in an individual, said methodcomprising prescribing or administering said low dosage formulation ofthe compound to said individual, wherein said individual has previouslybeen determined to have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In a sixty eighth aspect, a low dosage formulation of a compound for usein a method for treatment of obesity in an individual, wherein said lowdosage reduces or prevents a toxic event in said individual to saidcompound, wherein said individual has previously been determined to haverenal impairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In the fifty second through sixty eighth aspects, the followingembodiments, for example and without limitation, are envisioned. In someembodiments, said treatment of obesity comprises weight loss. In someembodiments, said treatment of obesity comprises maintenance of weightloss. In some embodiments, said treatment of obesity further comprises areduced-calorie diet. In some embodiments, said treatment of obesityfurther comprises a program of regular exercise. In some embodiments,said treatment of obesity further comprises both a reduced-calorie dietand a program of regular exercise. In some embodiments, said individualin need of treatment of obesity is an individual with an initial bodymass index ≧30 kg/m. In some embodiments, said individual in need oftreatment of obesity is an individual with an initial body mass index≧27 kg/m² in the presence of at least one weight related comorbidcondition. In some embodiments, said weight related comorbid conditionis selected from the group consisting of: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea. In someembodiments, the methods of the fifty second through sixty eighthaspects further comprise prescribing or administering phentermine tosaid individual. In some embodiments, the Cockcroft-Gault equation isused to determine the level of renal sufficiency of the individual. Insome embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in some embodiments the individual's actualbody weight is used in the Cockcroft-Gault equation. In someembodiments, the individual's serum creatinine concentration is used todetermine the level of renal sufficiency of the individual.

In a sixty ninth aspect, a method for prevention of obesity in anindividual in need thereof, comprising a) determining the level of renalsufficiency of the individual, and b) prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a seventieth aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD) is disclosed.

In a seventy first aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed.

In a seventy second aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a seventy third aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a seventy fourth aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation isdisclosed.

In a seventy fifth aspect, a method for prevention of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing or administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation isdisclosed.

In an seventy sixth aspect, a method for reducing the risk of an adverseevent in an individual in need for prevention of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment is disclosed.

In a seventy seventh aspect, a method for reducing the risk of anadverse event in an individual in need for prevention of obesity,comprising: a) determining the level of renal sufficiency of theindividual, and b) prescribing or administering a reduced dosage regimenof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable (salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment isdisclosed

In a seventy eighth aspect, a method for reducing the risk of an adverseevent in an individual in need for prevention of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In a seventy ninth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need for prevention of obesity, comprising:a) determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment is disclosed.

In an eightieth aspect, a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need for prevention of obesity, comprising:a) determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old        is disclosed

In an eighty first aspect, a compound for use in a method for preventionof obesity in an individual, said method comprising prescribing oradministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In an eighty second aspect, a compound for use in a method forprevention of obesity in an individual, said method comprisingprescribing or administering said compound at a dosage level appropriatefor the level of renal sufficiency of said individual, wherein saidindividual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, moderate renal impairment, severe renalimpairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In an eighty third aspect, a compound for use in a method for preventionof obesity in an individual, said method comprising determining thelevel of renal sufficiency of said individual and prescribing oradministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual has alevel of renal sufficiency selected from the group consisting of: norenal impairment, mild renal impairment, moderate renal impairment,severe renal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In an eighty fourth aspect, a low dosage formulation of a compound foruse in a method for prevention of obesity in an individual, said methodcomprising prescribing or administering said low dosage formulation ofthe compound to said individual, wherein said individual has previouslybeen determined to have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In an eighty fifth aspect, a low dosage formulation of a compound foruse in a method for prevention of obesity in an individual, wherein saidlow dosage reduces or prevents a toxic event in said individual to saidcompound, wherein said individual has previously been determined to haverenal impairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof isdisclosed.

In the fifty second through eighty fi aspects, the followingembodiments, for example and without limitation, are envisioned. In someembodiments, said prevention of obesity comprises weight loss. In someembodiments, said prevention of obesity comprises maintenance of weightloss. In some embodiments, said prevention of obesity further comprisesa reduced-calorie diet. In some embodiments, said prevention of obesityfurther comprises a program of regular exercise. In some embodiments,said prevention of obesity further comprises both a reduced-calorie dietand a program of regular exercise. In some embodiments, said individualin need for prevention of obesity is an individual with an initial bodymass index ≧27 kg/m² in the presence of at least one weight relatedcomorbid condition. In some embodiments, said weight related comorbidcondition is selected from the group consisting of: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea. In some embodiments, the methods of the fifty second througheighty fifth aspects further comprise prescribing or administeringphentermine to said individual. In some embodiments, the Cockcroft-Gaultequation is used to determine the level of renal sufficiency of theindividual. In some embodiments, the individual's ideal body weight isused in the Cockcroft-Gault equation and in some embodiments theindividual's actual body weight is used in the Cockcroft-Gault equation.In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows mean plasma concentration versus time profiles oflorcaserin after a 10 mg dose for groups 1-4 (group 1: normal renalfunction, group 2: mild renal impairment, group 3: moderate renalimpairment, group 4: severe renal impairment).

FIG. 1B shows mean plasma concentration versus time profiles oflorcascrin after a 10 mg dose for group 5 (group 5: end stage renaldisease, period 1 and period 2).

FIG. 1C shows mean plasma concentration versus time profiles of M1 aftera 10 mg dose for groups 1-4.

FIG. 1D shows mean plasma concentration versus time profiles of M1 aftera 10 mg dose for group 5.

FIG. 1E shows mean plasma concentration versus time profiles of M5 aftera 10 mg dose for groups 1-4.

FIG. 1F shows mean plasma concentration versus time profiles of M5 aftera 10 mg dose for group 5.

FIG. 2 shows renal clearance of lorcaserin as a function of creatinineclearance. The upper panel is for calculation uses ideal body weight andthe lower panel is for calculation using actual body weight.

FIG. 3 shows comparison of renal clearance and total clearance oflorcaserin using ideal body weight calculation.

FIG. 4 shows correlation of M1 exposure with creatinine clearance. Theleft panel shows results using ideal body weight and the right panelshows results using actual body weight.

FIG. 5 shows M5 exposure as a function of creatinine clearance.

FIG. 6 shows powder X-ray diffraction pattern (PXRD) of Compound 1Hydrochloride Hemihydrate, Form III.

FIG. 7 shows differential scanning calorimetry (DSC) of Compound 1Hydrochloride Hemihydrate, Form III.

FIG. 8 shows thermogravimetric analysis (TGA) of Compound 1Hydrochloride Hemihydrate, Form III.

FIG. 9 shows DMS dynamic moisture sorption (also called dynamic vaporsorption) of Compound 1 Hydrochloride Hemihydrate, Form III.

DETAILED DESCRIPTION

The interaction of renal sufficiency with the pharmacokinetics,tolerability and safety of lorcaserin has been assessed in a formalpharmacokinetic study in subjects with renal impairment and in thepopulations studied in phase 2 and phase 3 clinical studies. As shown inExample 2, lorcaserin exposure was not clearly affected by renalimpairment (Example 2) and total lorcaserin clearance was notsignificantly correlated with creatinine clearance (FIG. 3).

In contrast to the parent compound lorcaserin, the major circulatingmetabolite M1 (lorcaserin sulfamate) was significantly affected by renalimpairment. Although M1 is a minor metabolite in urine, plasma exposurewas increased in subjects with renal impairment (Example 3, Table 4 andFIGS. 1C, 1D). In addition, M1 exposure (AUC_(0-inf)) was significantlyinversely correlated with creatinine clearance and C_(max) was notcorrelated with creatinine clearance (Table 5, FIG. 4). Plasma exposureof M5 (N-carbamoyl glucuronide of lorcaserin), the major urinarymetabolite, was increased with increasing renal impairment. (FIG. 5,Table 6) and that M5 AUC_(0-inf), but not C_(max) was significantlycorrelated with creatinine clearance (Table 7).

Modeling of steady state exposures following lorcaserin 10 mg BID wasperformed using simulations and noncompartmental analysis based upondata from pharmacokinetic studies with once daily (QD) dosing (Table 8).For example, based on the modeled values, subjects with severe renalimpairment will reach M1 C_(max) levels of 1090 ng/mL (Table 8). ActualM1 levels over time in individuals with severe renal impairment was alsodetermined (Table 13). As shown in Table 13, the maximum individualC_(max) was more than five times the mean C_(max) for the subjectsstudied. Therefore some individuals could reach a level of five timesthe steady state mean level of 1090 ng/mL which is approximately theC_(max) in monkeys given the NOAEL dose (Table 9), leaving no marginbetween exposure levels at the NOAEL dose and projected exposure levelsin individuals with severe renal impairment.

In sum, based on clinical findings and the current guidance provided bythe Federal Drug Agency, no lorcaserin dose adjustment should be neededin individuals with mild or moderate renal impairment, but given thepredicted level of M1 and M5 in individuals with severe renalimpairment, lorcaserin should be used with caution in individuals withmoderate renal impairment and should not be used in individuals withsevere renal impairment or end stage renal disease (Example 7).

Definitions

ADMINISTERING: As used herein, “administering” means to provide acompound or other therapy, remedy or treatment. For example, a healthcare practitioner can directly provide a compound to an individual inthe form of a sample, or can indirectly provide a compound to anindividual by providing an oral or written prescription for thecompound. Also, for example, an individual can obtain a compound bythemselves without the involvement of a health care practitioner.Administration of the compound may or may not involve the individualactually internalizing the compound. In the case where an individualinternalizes the compound the body is transformed by the compound insome way.

ADVERSE EVENT OR TOXIC EVENT: As used herein, an “adverse event” or“toxic event” is any untoward medical occurrence that may present itselfduring treatment. Adverse events associated with treatment with Compound1 or a pharmaceutically acceptable salt, solvate or hydrate thereof aredisclosed herein, for example, in Example 6 and Table 11. Possibleadverse events disclosed in Example 6 include, abdominal pain, diarrhea,dyspepsia, stomach discomfort, and worsening renal impairment,dizziness, headache. Other possible adverse events based on observationsfrom studies in monkeys include emesis, decreased food intake, weightloss, decreased activity, spontaneous penile erection, tremors orseizures. Additional possible adverse events include, for example,nausea, blurred vision, paresthesias, dry mouth and fatigue. In themethods disclosed herein, the term adverse event can be replaced byother more general terms such as toxicity. The term “reducing the risk”of an adverse event means reducing the probability that an adverse eventor toxic event could occur.

INDIVIDUAL: As used herein, an “individual” is a human. An individualcan be an adult or prepubertal (a child) and can be of any gender. Theindividual can be a patient or other individual seeking treatment. Themethods disclosed herein can also apply to non-human mammals such aslivestock or pets.

LEVEL OF RENAL SUFFICIENCY: As used herein, the term “level of renalsufficiency” means the level of renal (kidney) function in anindividual. As used herein, the levels of renal sufficiency in anindividual include: no renal impairment, mild renal impairment, moderaterenal impairment, severe renal impairment and end stage renal disease(ESRD). The term renal impairment includes mild renal impairment,moderate renal impairment, severe renal impairment and end stage renaldisease (ESRD).

PLURALITY OF INDIVIDUALS: As used herein, a “plurality of individuals”means more than one individual.

PRESCRIBING: As used herein, “prescribing” means to order, authorize orrecommend the use of a drug or other therapy, remedy or treatment. Insome embodiments, a health care practitioner can orally advise,recommend or authorize the use of a compound, dosage regimen or othertreatment to an individual. In this case the health care practitionermay or may not provide a prescription for the compound, dosage regimenor treatment. Further the health care practitioner may or may notprovide the recommended compound or treatment. For example, the healthcare practitioner can advise the individual where to obtain the compoundwithout providing the compound. In some embodiments, a health carepractitioner can provide a prescription for the compound, dosage regimenor treatment to the individual. For example, a health care practitionercan give a written or oral prescription to an individual. A prescriptioncan be written on paper or on electronic media such as a computer file,for example, on a hand held computer device. For example, a health carepractitioner can transform a piece of paper or electronic media with aprescription for a compound, dosage regimen or treatment. In addition, aprescription can be called in (oral) or faxed in (written) to a pharmacyor a dispensary. In some embodiments, a sample of the compound ortreatment can be given to the individual. As used herein, giving asample of a compound constitutes an implicit prescription for thecompound. Different health care systems around the world use differentmethods for prescribing and administering compounds or treatments andthese methods are encompassed by the disclosure.

A prescription can include, for example, an individual's name and/oridentifying information such as date of birth. In addition, for example,a prescription can include, the medication name, medication strength,dose, frequency of administration, route of administration, number oramount to be dispensed, number of refills, physician name, physiciansignature. Further, for example, a prescription can include a DEA numberor state number.

PREVENTION: As used herein, the term “prevention” such as prevention ofobesity means prevention of the occurrence or onset of one or moresymptoms associated with a particular disorder and does not necessarilymean the complete prevention of a disorder. For example, the term“prevent,” “preventing” and “prevention” refers to the administration oftherapy on a prophylactic or preventative basis to an individual who mayultimately manifest at least one symptom of a disease or condition butwho has not yet done so. Such individuals can be identified on the basisof risk factors that are known to correlate with the subsequentoccurrence of the disease. Alternatively, prevention therapy can beadministered without prior identification of a risk factor, as aprophylactic measure. Delaying the onset of the at least one symptom canalso be considered prevention or prophylaxis.

As used herein, “prevention of obesity in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from prevention of obesity. Thisjudgment is made based on a variety of factors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition that is treatable by the methodsdisclosed herein.

REDUCED DOSAGE REGIMEN: A “reduced dosage regimen” as used herein meansa reduction in the amount of a compound such as Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof that anindividual is prescribed or administered in a fixed time period comparedto the recommended dosage regimen. In some embodiments, the reduction inthe amount of a compound that an individual is administered in a fixedtime period compared to the recommended dosage is accomplished byreducing the amount of Compound 1 in each unit dose. For example, onerecommended dosage regimen for Compound 1 or a pharmaceuticallyacceptable salt, solvate or hydrate thereof is a 10 mg capsule takentwice a day. A reduced dosage regimen can be a capsule (unit dose) withless than 10 mg taken twice a day, for example, a capsule with 9 mg, 8mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg or less than 1 mg takentwice a day. A capsule (unit dose) with less than 10 mg is an example ofa low dosage formulation. In some embodiments, the reduction in theamount of a compound that an individual is administered in a fixed timeperiod compared to the recommended dosage is accomplished by increasingthe time interval between doses. For example, a 10 mg capsule can beadministered once per day instead of twice per day to effectively reducethe dose. In addition, both a decrease in the amount of compound perunit dose and an increase the time interval between doses can be used.Since dosing can be dependent on body weight, it may be that arecommended dosage regimen is expressed in mg of compound per kg of bodyweight instead of a fixed amount of compound for all individuals. Areduction in the mg of compound per kg of body weight is an example of areduced dosage regimen. Any embodiment that employs a reduced dosageregimen can equally employ a low dosage formulation.

RENAL IMPAIRMENT: As used herein, “no renal impairment” means theindividual has normal renal function. Levels of renal function, renalsufficiency or renal impairment can be determined using any of themethods known in the art or described herein. Regarding terms such as“mild renal impairment”, “moderate renal impairment”, “severe renalimpairment” and “end stage renal disease (ESRD)” cut-offs to definethese levels of renal sufficiency are dependent on the test done todetermine the level of renal sufficiency.

Different thresholds or cutoffs can be used to determine the level ofrenal sufficiency in an individual depending on the technique used andthe interpretation of the health care practitioner. Several variablescan be considered when determining the level of renal sufficiency in anindividual including, for example, whether an individual is obese, theindividual's race, the individual's gender, and the individual's age.Recommendations regarding classification of renal sufficiency are knownin the art. These recommendations may change over time as newertechniques or better equations are used to more accurately determinerenal function in an individual.

SATIETY: As used herein, “satiety” is the quality or state of being fedor gratified to or beyond capacity. Satiety is a feeling that anindividual has and so it is often determined by asking the individual,orally or in writing, if they feel full, sated, or satisfied at timedintervals during a meal. For example, an individual who feels sated mayreport feeling full, feeling a decreased or absent hunger, feeling adecreased or absent desire to eat, or feeling a lack of drive to cat.While fullness is a physical sensation, satiety is a mental feeling. Anindividual who feels full, sated or satisfied is more likely to stopeating and therefore inducing satiety can result in a decrease in foodintake in an individual.

As used herein, “inducing satiety in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from inducing satiety. This judgmentis made based on a variety of factors that are in the realm of ahealthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition, for example, obesity, that istreatable by the methods of the disclosure.

THERAPEUTICALLY EFFECTIVE AMOUNT: The term “therapeutically effectiveamount” refers to the amount of active compound or pharmaceutical agentthat elicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician or caregiver or by anindividual, which includes one or more of the following:

(1) Preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

TREAT, TREATING, OR TREATMENT: As used herein the term “treat,”“treating” or “treatment” refers to the administration of therapy to anindividual who already manifests at least one symptom of a disease orcondition or who has previously manifested at least one symptom of adisease or condition. For example, “treating” can include alleviating,abating or ameliorating a disease or condition symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition, relieving the disease orcondition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptomsof the disease or condition either prophylacticly and/ortherapeutically. For example, the term “treating” in reference to adisorder means a reduction in severity of one or more symptomsassociated with a particular disorder. Therefore, treating a disorderdoes not necessarily mean a reduction in severity of all symptomsassociated with a disorder and does not necessarily mean a completereduction in the severity of one or more symptoms associated with adisorder. For example, a method for treatment of obesity can result inweight loss; however, the weight loss does not need to be enough suchthat the individual is no longer obese. It has been shown that evenmodest decreases in weight or related parameters such as BMI, waistcircumference and percent body fat, can result in improvement of health,for example, lower blood pressure, improved blood lipid profiles, or areduction in sleep apnea.

As used herein, “treatment of obesity in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from treatment of obesity. Thisjudgment is made based on a variety of factors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition that is treatable by the methods ofthe disclosure.

WEIGHT MANAGEMENT: As used herein, the term “weight management” meanscontrolling body weight and in the context of the present disclosure isdirected toward weight loss and the maintenance of weight loss (alsocalled weight maintenance herein). In addition to controlling bodyweight, weight management includes controlling parameters related tobody weight, for example, BMI, percent body fat and waist circumference.For example, weight management for an individual who is overweight orobese can mean losing weight with the goal of keeping weight in ahealthier range. Also, for example, weight management for an individualwho is overweight or obese can include losing body fat or circumferencearound the waist with or without the loss of body weight.

Maintenance of weight loss (weight maintenance) includes preventing,reducing or controlling weight gain after weight loss. It is well knownthat weight gain often occurs after weight loss. Weight loss can occur,for example, from dieting, exercising, illness, drug treatment, surgeryor any combination of these methods, but often an individual that haslost weight will regain some or all of the lost weight. Therefore,weight maintenance in an individual who has lost weight can includepreventing weight gain after weight loss, reducing the amount of weightgained after weight loss, controlling weight gain after weight loss orslowing the rate of weight gain after weight loss.

As used herein, “weight management in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from weight management treatment.This judgment is made based on a variety of factors that are in therealm of a healthcare practitioner's expertise, but that includes theknowledge that the individual has a condition that is treatable by themethods disclosed herein.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers but not the exclusionof any other step or element or integer or group of elements orintegers.

Throughout this specification, unless specifically stated otherwise orthe context requires otherwise, reference to a single step, compositionof matter, group of steps or group of compositions of matter shall betaken to encompass one and a plurality (i.e. one or more) of thosesteps, compositions of matter, groups of steps or group of compositionsof matter.

Each embodiment described herein is to be applied mutatis mutandis toeach and every other embodiment unless specifically stated otherwise.

Those skilled in the art will appreciate that the invention(s) describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the invention(s)includes all such variations and modifications. The invention(s) alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of said steps or featuresunless specifically stated otherwise.

The present invention(s) is not to be limited in scope by the specificembodiments described herein, which are intended for the purpose ofexemplification only. Functionally-equivalent products, compositions andmethods are clearly within the scope of the invention(s), as describedherein.

It is appreciated that certain features of the invention(s), which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the invention(s), which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination. For example, a method that recitesprescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine can beseparated into two methods; one reciting prescribing(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and the otherreciting administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. In addition,for example, a method that recites prescribing(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and a separatemethod of the invention reciting administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine can becombined into a single method reciting prescribing and/or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

The selective 5-HT_(2C)-receptor agonist(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine (Compound 1),is useful for, inter alia, weight management, including weight loss andmaintenance of weight loss (weight maintenance). Compound 1 is disclosedin PCT patent publication WO2003/086303, which is incorporated herein byreference in its entirety.

Various synthetic routes to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its relatedsalts, enantiomers, crystalline forms, and intermediates, have beenreported in WO 2005/019179, WO2006/069363, WO2007/120517, WO2008/070111,and WO2009/111004 each of which is incorporated herein by reference inits entirety.

Combinations of (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepinewith other agents, including without limitation, phentermine, and usesof such combinations in therapy are described in WO2006/071740, which isincorporated herein by reference in its entirety.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(lorcaserin hydrochloride) is an agonist of the 5-HT_(2C) receptor andshows effectiveness at reducing obesity in animal models and humans. InDecember 2009, Arena Pharmaceuticals submitted a New Drug Application,or NDA, for lorcaserin to the FDA. The NDA submission is based on anextensive data package from lorcaserin's clinical development programthat includes 18 clinical trials totaling 8,576 patients. The pivotalphase 3 clinical trial program evaluated nearly 7,200 patients treatedfor up to two years, and showed that lorcaserin consistently producedsignificant weight loss with excellent tolerability. About two-thirds ofpatients achieved at least 5% weight loss and over one-third achieved atleast 10% weight loss. On average, patients lost 17 to 18 pounds orabout 8% of their weight. Secondary endpoints, including bodycomposition, lipids, cardiovascular risk factors and glycemic parametersimproved compared to placebo. Heart rate and blood pressure went down.Lorcaserin did not increase the risk of cardiac valvulopathy. Lorcaserinimproved quality of life, and there was no signal for depression orsuicidal ideation. The only adverse event that exceeded the placebo rateby 5% was generally mild or moderate, transient headache. Based on anormal BMI of 25, patients in the first phase 3 trial lost aboutone-third of their excess body weight. The average weight loss was 35pounds or 16% of body weight for the top quartile of patients in thesecond phase 3 trial.

Throughout this application the compound(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is alsoreferred to as “Compound 1”. Therefore, “Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof” is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Likewise,“Compound 1 hydrochloride and hydrates thereof” is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof. Further, “Compound 1 hydrochloride hemihydrate” is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate and “Compound 1 hydrochloride hemihydrate, Form III” is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine hydrochloridehemihydrate, Form III.

In some embodiments, the terms“(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate, or hydrate thereof” and“(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, andpharmaceutically acceptable salts, solvates, and hydrates thereof” asused herein encompass any one of the following salts, or a Markush groupcomprising any combination of the following salts:

-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hydroiodide salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate    salt; and-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemifumarate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    di-acetamidobenzoate salt-cocrystal;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    trans-cinnamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    heminapadisilate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    (±)-mandelate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemipamoate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    (1S)-(+)-10-camsylate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemi-L-malate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    L-glutamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    L-aspartate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    pyroglutamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    glucuronate salt; and-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    di-camphorate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine bisulfate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemisulfate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine mesylate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hydrobromide salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    sesqui-oxalate salt-cocrystal;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine malonate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemimalonate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemi-edisylate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine    hemi-oxalate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate    salt; and-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    oxoglutarate salt; and-   pharmaceutically acceptable solvates and hydrates thereof.

In some embodiments, the terms“(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate, or hydrate thereof” and“(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, andpharmaceutically acceptable salts, solvates, and hydrates thereof” asused herein encompass any one of the following salts, or a Markush groupcomprising any combination of the following salts:

-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hydroiodide salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemifumarate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate    salt hydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    trans-cinnamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    heminapadisilate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    heminapadisilate salt solvate 1;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    heminapadisilate salt solvate 2;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    (t)-mandelate salt hydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemipamoate salt hydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-11H-3-benzazepine    (1S)-(+)-10-camsylate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemi-L-malate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    L-glutamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    L-aspartate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    pyroglutamate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    glucuronate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    di-camphorate salt solvate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine bisulfate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemisulfate salt hydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine mesylate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hydrobromide salt hemihydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    sesqui-oxalate salt-cocrystal;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine malonate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemimalonate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine    hemi-edisylate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate    salt hemihydrate;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    hemi-oxalate salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate    salt;-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    oxoglutarate salt; and-   (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine    oxoglutarate salt solvate.

The preceding salts were prepared and characterized using the followingexperimental procedures and physicochemical data.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodidesalt was prepared by the dropwise addition of one equivalent of aqueousH1 (˜57%) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inisopropyl acetate. A precipitate formed after 7 days stirring withevaporation. The solid was slurried in ethyl acetate with ˜3% wateradded for 5 h. The solid was recovered by centrifuge filtration (10,000rpm for 1 minute, nylon filter).(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodidesalt had an extrapolated melting onset temperature by DSC of 155-156° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate saltwas prepared by dropwise addition of a solution of 1 or 2 equivalents ofmaleic acid in methanol to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inisopropyl acetate or acetonitrile with vigorous stirring. The resultingslurry was heated to 60° C. and held at that temperature for ˜1 h beforeit was cooled to room temperature and stirred overnight. The title saltwas recovered by filtration, washed with isopropyl acetate oracetonitrile and dried on the filter before characterization.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salthad an extrapolated melting onset temperature by DSC of about 166° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate saltwas prepared by dropwise addition of an equimolar amount of fumaric acidin 1:1 water:EtOH (˜0.6 M) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate with vigorous stirring. The resulting suspension was heated to60° C., held at that temperature for 1 h, and then allowed to cool toambient temperature while stirring overnight. The mixture was filteredand the solid was washed with isopropyl acetate and dried on the filter.Alternatively, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinefumarate salt was prepared by adding either a half molar or an equimolaramount of dry solid fumaric acid to solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. The mixture was slurried at ˜60° C. and stirred for ˜2 h. Theheat source was removed and the mixture was left to stir for 3 days at˜26° C. The solid precipitate was recovered by filtration, and thenre-slurried for ˜24 h in water or ethanol. The solid was recovered byfiltration and slurried for an additional 4 days in n-propanol,acetonitrile, or water.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salthad an extrapolated melting onset temperature by DSC of 218-219° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumaratesalt was prepared by dropwise addition of a half-molar amount of fumaricacid in 1:1 water:EtOH (˜0.6 M) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate with vigorous stirring. A suspension resulted. It was heated to60° C., held at that temperature for 1 h, and then the heat source wasremoved and the sample was allowed to cool to ambient temperature whilestirring overnight. The suspension was filtered and the solid was washedwith isopropyl acetate and dried on the filter.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumaratesalt had an extrapolated melting onset temperature by DSC of 158° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine orotate saltwas prepared by addition of one equivalent of orotic acid to a solutionof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inisopropanol, ethyl acetate, or acetone at 60° C. Orotic acid, at 60° C.,was added drop-wise, in the corresponding solvent, with vigorousstirring. Precipitation occurred immediately and the suspension wasallowed to cool and stir overnight. The resulting solid was recovered byfiltration and air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salthad an extrapolated initial melting onset temperature by DSC of 236° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salthydrate was prepared by addition of one equivalent of orotic acid to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile or isopropanol at 60° C. Orotic acid, at 60° C., was addeddrop-wise, in the corresponding solvent, with vigorous stirring.Precipitation occurred immediately and the suspension was allowed tocool and stir overnight. Compound 1 orotate salt hydrate prepared inisopropanol consisted of a mixture of the anhydrous and hydrated formswhich was converted to the hydrated form by slurring in isopropanol fortwo days. Alternatively,(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salthydrate was prepared by slurrying anhydrous(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate saltin water. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineorotate salt hydrate had an extrapolated melt/recrystallization onsettemperature by DSC of 173° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinedi-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate wasprepared by combining one equivalent of 4-acetamidobenzoic acid with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in n-propanolor methanol at 50° C. then cooling slowly and stirring overnight. Theresulting clear solution was evaporated to a mixture of oil and solids.Upon trituration with MEK a white solid formed and was filtered anddried. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinedi-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate had anextrapolated melting/desolvation onset temperature by DSC of 113° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinetrans-cinnamate salt was prepared by combining one equivalent oftrans-cinnamic acid with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile at 50° C. The sample was cooled slowly and stirredovernight. The resulting white solid was isolated by filtration anddried. Similar samples prepared in isopropanol, acetone or THF producedwhite solids only after removal of solvent and trituration with MTBE.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinetrans-cinnamate salt had an extrapolated melting onset temperature byDSC of 106° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt was prepared by addition of a molar equivalent ofnaphthalene-1,5-disulfonic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropanolor acetonitrile at 60° C. Naphthalene-1,5-disulfonic acid, at 60° C.,was added drop-wise, in the corresponding solvent, with vigorousstirring. Precipitation occurred immediately in acetonitrile and thesuspension was allowed to cool and stir overnight. Addition of waterprecipitated the salt in isopropanol and the suspension was allowed tocool and stir overnight. The resulting solid was recovered by filtrationand air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt had an extrapolated melting onset temperature byDSC of about 266° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt solvate 1 was prepared by addition of oneequivalent of naphthalene-1,5-disulfonic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethylacetate at 60° C. Naphthalene-1,5-disulfonic acid in ethyl acetate, at60° C., was added dropwise with vigorous stirring. Precipitationoccurred immediately and the suspension was allowed to cool and stirovernight. The resulting solid was recovered by filtration and air-driedin a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt solvate 1 had an extrapolated desolvation onsettemperature by DSC of about 101° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt solvate 2 was prepared by the addition of oneequivalent of naphthalene-1,5-disulfonic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in acetone at60° C. Naphthalene-1,5-disulfonic acid in acetone at 60° C. was addeddropwise with vigorous stirring. A yellow oil precipitated and thesuspension was allowed to cool and stir overnight. A white precipitatewas observed after stirring overnight. The resulting solid was recoveredby filtration and air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineheminapadisilate salt solvate 2 had an extrapolated desolvation onsettemperature by DSC of about 129° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (t)-mandelatesalt hydrate was prepared by the addition of one equivalent of(±)-mandelic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile, ethyl acetate, or acetone at 60° C. (±)-Mandelic acid, at60° C., was added dropwise, in the corresponding solvent, with vigorousstirring. Addition of water to these three samples precipitated the saltand it was allowed to cool and stir overnight. The resulting solids wererecovered by filtration and air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (±)-mandelatesalt hydrate had an extrapolated desolvation onset temperature by DSC ofabout 74° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoatesalt hydrate was prepared by the addition of 0.25 molar equivalents ofpamoic acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inisopropanol, acetonitrile, ethyl acetate, or acetone at 60° C. Pamoicacid, at 60° C., was added dropwise, in the corresponding solvent, withvigorous stirring. Precipitation occurred immediately and the suspensionwas allowed to cool and stir overnight. The resulting solid wasrecovered by filtration and air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoatesalt hydrate had an extrapolated melting onset temperature by DSC ofabout 244° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt was prepared by the dropwise addition of 1mole equivalent of ˜3.6 M aqueous (1S)-(+)-10-camphorsulfonic acid to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile with vigorous stirring. Immediate precipitation wasobserved and the solid was collected by filtration and washed withisopropyl alcohol.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(1S)-(+)-10-camsylate salt had an extrapolated melting onset temperatureby DSC of about 176° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt was prepared by the dropwise addition of L-malic acid (0.5 eq.),either in solution in hot MeOH or as a solid, to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. The mixture was heated to ˜60° C. and held at that temperaturefor ˜1 h. The mixture was then allowed to cool to room temperature andstirred for 1-3 days. The solid product was isolated by vacuumfiltration and dried on the filter or in an oven at 40° C.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malatesalt had an extrapolated melting onset temperature by DSC of 155-156° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt was prepared by addition of L-glutamic acid (0.5-1 eq.) in hotEtOH/H₂O (˜2:1) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate, followed by evaporation of the solvent overnight to produce asolid. The solid was slurried in isopropyl acetate and then isolated byfiltration. Alternatively,(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt was prepared by addition of a solution of L-glutamic acid (1 eq.)in hot H₂O to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The productcrystallized without the need for evaporation of the solvent.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamatesalt had an extrapolated melting onset temperature by DSC of about 187°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt was prepared by addition of a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in eitheracetone or acetonitrile to one equivalent of aspartic acid solid. Themixture was heated to 50° C. then slow-cooled and stirred overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartatesalt had an extrapolated melting onset temperature by DSC of about 174°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucatesalt was synthesized from(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine (2 equivalents)and mucic acid (I equivalent) in THF, acetone or IPA (˜10 mg/mL) with 4%water. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimucate salt had an extrapolated melting onset temperature by DSC ofabout 208° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronatesalt was prepared by addition of a molar equivalent of D-glucuronic acidto a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inisopropanol, acetonitrile, ethyl acetate, or acetone at 60° C.D-glucuronic acid, dissolved in the corresponding solvent at 60° C., wasadded dropwise with vigorous stirring. Precipitation occurredimmediately and the suspension was allowed to cool and stir overnight.The resulting solid was recovered by filtration and dried in a fume hoodovernight. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineglucuronate salt had an extrapolated melting onset temperature by DSC ofabout 164° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt was prepared by combining one equivalent of pyroglutamic acid with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethylacetate at 60° C. then cooling slowly and stirring overnight. Theresulting white solid was isolated by filtration and dried.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamatesalt had an extrapolated melting onset temperature by DSC of about 139°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt solvate was prepared by combining equal molar amounts of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and(1R,3S)-(+)-camphoric acid in ethyl acetate with 4% water. The solutionwas heated to 50° C. then slowly cooled. Upon cooling the sample was aclear solution and did not change after addition of MTBE. The sample wasevaporated to a clear oil which formed a white solid after standing atroom temperature.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphoratesalt had an extrapolated melting onset temperature by DSC of about 90°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine bisulfate saltwas prepared by drop-wise addition of 1 mole equivalent of concentratedsulfuric acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base ineither isopropyl acetate or acetonitrile with vigorous stirring.Precipitation occurred immediately and the suspension was allowed tostir for 1 to 2 days. The resulting solid was recovered by filtration.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine bisulfate salthad an extrapolated melting onset temperature by DSC of about 162° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemisulfatesalt was prepared by the drop-wise addition of 0.5 mole equivalent ofconcentrated sulfuric acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base ineither isopropyl acetate or acetonitrile with vigorous stirring.Precipitation occurred immediately and the suspension was allowed tostir for 1 to 2 days. The resulting yellow solid was recovered byfiltration. Acetone was added to the solid followed by sufficient waterto cause dispersal (<5%). This mixture was slurried for 4 h and thesolid was collected by centrifuge filtration (10,000 rpm for 1 min). Thefiltrate contained an oil droplet and the filter cake had a small amountof color at the bottom. The white upper portion of the filter cake wasremoved and air-dried overnight to leave the title salt as a whitesolid. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemisulfate salt had an extrapolated melting onset temperature by DSC ofabout 79° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine mesylate saltwas prepared by the dropwise addition of one equivalent ofmethanesulfonic acid (99.5%) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inacetonitrile, or isopropyl acetate with vigorous stirring.Crystallization occurred either immediately or within 24 hours after thesolution was heated to ˜60° C. and then allowed to cool to RT whilestirring. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinemesylate salt had an extrapolated melting onset temperature by DSC ofabout 178° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine hydrobromidesalt hemihydrate was prepared by the dropwise addition of one equivalentof aqueous HBr (˜48%) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inisopropyl acetate, acetonitrile, or ethyl acetate with vigorousstirring. The product readily precipitated from the reaction inisopropyl acetate. In acetonitrile the solvent was evaporated to neardryness to obtain a solid. In ethyl acetate, seeds were added and thereaction was allowed to stir unstoppered to initiate crystallization.The reaction was then closed and stirring was continued to afford ayellow suspension. The suspension was filtered and the solid was washedwith cold ethyl acetate. The resulting white solid was under nitrogen at˜38° C., and held overnight at 25° C./75% RH.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromidesalt hemihydrate had an extrapolated dehydration onset temperature byTGA of about 72.5° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate saltwas prepared by dropwise addition of aqueous HNO₃ to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inisopropyl acetate or acetonitrile with vigorous stirring.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate salthad an extrapolated melting onset temperature by DSC of about 124° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine sesqui-oxalatesalt-cocrystal was prepared by addition of oxalic acid (0.5 eq.) to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine inisopropyl acetate.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine sesqui-oxalatesalt-cocrystal had an initial endotherm with an extrapolated onsettemperature by DSC of about 105° C. and a second endotherm with anextrapolated melting onset temperature by DSC of about 111° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate saltwas prepared by addition of adipic acid (0.5-1 eq.) in acetone to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine at˜62° C. Precipitation occurred within 5 min and the suspension wasallowed to cool to ambient temperature with stirring.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate salthad multiple endothermic events by DSC starting at onset temperaturesbetween 104° C. and 107° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine malonate saltwas prepared by addition of malonic acid (1 eq.) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinemalonate salt had an extrapolated melting onset temperature by DSC ofabout 143° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimalonatesalt was prepared by addition of malonic acid (0.5 eq.) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemimalonate salt had an extrapolated melting onset temperature by DSCof 135-136° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate saltwas prepared by the addition of one equivalent of glycolic acid to asolution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inethyl acetate or acetone at 60° C. Glycolic acid, at 60° C., was addeddropwise, in the corresponding solvent, with vigorous stirring.Precipitation occurred immediately and the suspension was allowed tocool and stir overnight. The resulting solid was recovered by filtrationand air-dried in a fume hood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate salthad an extrapolated melting onset temperature by DSC of about 138° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-edisylatesalt was prepared by the dropwise addition of 0.5 equivalents of aqueous1,2-ethanedisulfonic acid dihydrate (˜3.7 M) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base ineither acetonitrile or isopropyl acetate with vigorous stirring.Immediate precipitation was observed. The solid obtained was washed withisopropyl alcohol and allowed to dry on the filter.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-edisylatesalt had an extrapolated melting onset temperature by DSC of about 298°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate saltwas prepared by dropwise addition of ortho-phosphoric acid (85%) (0.5-1mole equivalent) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base inisopropyl acetate or acetonitrile with vigorous stirring. Immediateprecipitation was observed in all experiments. Initially amorphousmaterial was slurried in acetone; initially crystalline material wasslurried/ripened in n-propanol for 3 days.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate salthad an extrapolated melting onset temperature by DSC of about 208° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate salthemihydrate was prepared by dropwise addition of 1 mole equivalent ofcitric acid in hot MeOH to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. Precipitation occurred spontaneously.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate salthemihydrate had a dehydration onset temperature by DSC of about 80° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-oxalatesalt was prepared by dropwise addition of 1 mole equivalent of oxalicacid as a solid or as a solution in MeOH (˜2.5 M) to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropylacetate. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemi-oxalate salt had an extrapolated melting onset temperature by DSCof about 212° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate saltwas prepared by the addition of succinic acid (0.5-1 eq.) in hot EtOH toa solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinein isopropyl acetate. After overnight stirring, a solid was recovered bysuction filtration and washed in isopropyl acetate.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate salthad an extrapolated melting onset temperature by DSC of about 179.1° C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutaratesalt was prepared by addition of one equivalent of α-oxo-glutaric acidto a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethylacetate at 60° C. α-Oxo-glutaric acid in ethyl acetate at 60° C. wasadded dropwise with vigorous stirring. Precipitation occurredimmediately and the suspension was allowed to cool and stir overnight.The resulting solid was recovered by filtration and air-dried in a fumehood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutaratesalt had an extrapolated melting onset temperature by DSC of about 115°C.

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutaratesalt solvate was prepared by addition of a molar equivalent ofα-oxo-glutaric acid to a solution of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine inacetonitrile at 60° C. α-Oxo-glutaric acid in acetonitrile at 60° C. wasadded dropwise with vigorous stirring. Precipitation occurredimmediately and the suspension was allowed to cool and stir overnight.The resulting solid was recovered by filtration and air-dried in a fumehood overnight.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutaratesalt solvate had an extrapolated desolvation onset temperature by DSC ofabout 91° C., and a second endotherm with an extrapolated onsettemperature by DSC of about 113° C.

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates and hydrates” or the phrase “pharmaceutically acceptablesalt, solvate or hydrate” is used when referring to compounds describedherein, it embraces pharmaceutically acceptable solvates and/or hydratesof the compounds, pharmaceutically acceptable salts of the compounds, aswell as pharmaceutically acceptable solvates and/or hydrates ofpharmaceutically acceptable salts of the compounds. It is alsounderstood that when the phrase “pharmaceutically acceptable solvatesand hydrates” or the phrase “pharmaceutically acceptable solvate orhydrate” is used when referring to compounds described herein that aresalts, it embraces pharmaceutically acceptable solvates and/or hydratesof such salts.

It will be apparent to those skilled in the art that the dosage formsdescribed herein may comprise, as the active component, either acompound described herein or a pharmaceutically acceptable salt or as asolvate or hydrate thereof. Moreover, various hydrates and solvates ofthe compounds described herein and their salts will find use asintermediates in the manufacture of pharmaceutical compositions. Typicalprocedures for making and identifying suitable hydrates and solvates,outside those mentioned herein, are well known to those in the art; seefor example, pages 202-209 of K. J. Guillory, “Generation of Polymorphs,Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism inPharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker,Inc., New York, 1999. Accordingly, one aspect of the present disclosurepertains to methods of administering hydrates and solvates of compoundsdescribed herein and/or their pharmaceutical acceptable salts, that canbe isolated and characterized by methods known in the art, such as,thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infraredspectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration,high resolution X-ray diffraction, and the like. There are severalcommercial entities that provide quick and efficient services foridentifying solvates and hydrates on a routine basis. Example companiesoffering these services include Wilmington PharmaTech (Wilmington,Del.), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, Conn.).

The present disclosure includes all isotopes of atoms occurring in thepresent compounds, salts and crystalline forms thereof. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example, and without limitation, isotopes of hydrogeninclude ²H (deuterium) and ³H (tritium). Isotopes of carbon include ¹³Cand ¹⁴C.

Generally, disclosed herein are methods for treating an indication,comprising determining the level of renal sufficiency of the individualand prescribing or administering a compound such as Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual. Several indications are encompassed as well as severaldifferent methods of determining the level of renal sufficiency of theindividual, and different remedies are prescribed or administered to theindividual. As disclosed above, certain features of the methods, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the methods, which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Regarding indications, the disclosure encompasses a method for weightmanagement in an individual in need thereof, decreasing food intake inan individual, inducing satiety in an individual, for the treatment ofobesity, and the prevention of obesity. In addition, the disclosureencompasses a method of weight loss in an individual or method formaintenance of weight loss in an individual. Further, the disclosureencompasses a method of treating an individual in need of treatment withCompound 1 or a pharmaceutically acceptable salt, solvate or hydratethereof, and of treating a disorder related to 5-HT_(2C) receptoractivity. Any of these indications can be combined with any of themethods of determining the level of renal sufficiency in an individual,and any remedy prescribed or administered to the individual unlessspecifically stated otherwise or the context requires otherwise.

Regarding the methods of determining if the level of renal sufficiencyin an individual, in some embodiments the level of renal sufficiency isdetermined by the Cockcroft-Gault equation which can be calculated usingthe individual's actual, ideal or otherwise adjusted body weight. Inother embodiments the level of renal sufficiency is determined bycalculating the glomerular filtration rate (GFR) of the individual byone of many methods known in the art such as using a radioactivelylabeled marker. The GFR can also be estimated using the Cockcroft-Gaultequation or the modification of diet in renal disease (MDRD) formula,usually calculated with 4 or 6 variables. The serum creatinineconcentration of the individual can also be used to determine the levelof renal sufficiency of an individual. In some embodiments, the methodof determining the level of renal sufficiency in the individual is notspecified. In some embodiments the individual is asked about their levelof renal sufficiency either orally or on a form.

The levels of renal sufficiency of an individual can include, forexample, no renal impairment (i.e., normal renal function), mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD.In some embodiments, the level of renal sufficiency is not specified.The methods herein can comprise prescribing or administering differentremedies such as Compound 1 or a pharmaceutically acceptable salt,solvate or hydrate thereof, Compound 1 hydrochloride and hydratesthereof, Compound 1 hydrochloride hemihydrate or Compound 1hydrochloride hemihydrate, Form III. The method can also compriseprescribing or administering a reduced dosage regimen of Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof, or ananti-obesity drug other than Compound 1 or a pharmaceutically acceptablesalt, solvate or hydrate thereof, or a reduced-calorie diet and/orregular exercise program.

Disclosed herein is a method for weight management in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Also disclosed is a method for weight management in an individual inneed thereof, comprising: a) determining the level of renal sufficiencyof the individual, and b) prescribing a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. In addition,disclosed herein is a method for weight management in an individual inneed thereof, comprising: a) determining the level of renal sufficiencyof the individual, and b) administering a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

In addition, disclosed herein is a method for weight management in anindividual in need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for weight management in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) prescribing therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD. In addition, disclosed herein is a method for weightmanagement in an individual in need thereof, comprising: a) determiningthe level of renal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

If it is determined that(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof can safelybe given to an individual with severe renal impairment in any aspect orembodiment of the disclosure that includes prescribing or administeringor otherwise using the compound for individuals with severe renalimpairment or ESRD, the disclosure specifically embraces justprescribing or administering or otherwise using the compound forindividuals with ESRD.

Therefore, for example, the disclosure provides a method for weightmanagement in an individual in need thereof, comprising: a) determiningthe level of renal sufficiency of the individual, and b) prescribingtherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have ESRD. Inaddition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have ESRD.

Likewise any aspect or embodiment of the disclosure that includesprescribing or administering or otherwise using the compound forindividuals with a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment, the disclosure specifically embraces prescribing oradministering or otherwise using the compound for individuals with alevel of renal sufficiency selected from the group consisting of norenal impairment, mild renal impairment, moderate renal impairment andsevere renal impairment.

Therefore, for example, the disclosure provides a method for weightmanagement in an individual in need thereof, comprising: a) determiningthe level of renal sufficiency of the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, moderate renal impairment, and severe renalimpairment. In addition, the disclosure provides a method for weightmanagement in an individual in need thereof, comprising: a) determiningthe level of renal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, moderate renal impairment and severe renalimpairment.

Similarly, in some embodiments, the individual has ESRD.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate, Form III (as described herein).

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual.

In some embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in other embodiments the individual'sactual body weight is used in the Cockcroft-Gault equation.

In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

As used herein, the term “weight management” means controlling bodyweight and in the context of the present disclosure is directed towardweight loss and the maintenance of weight loss (also called weightmaintenance herein). In addition to controlling body weight, weightmanagement includes controlling parameters related to body weight, forexample, BMI, percent body fat and waist circumference. For example,weight management for an individual who is overweight or obese can meanlosing weight with the goal of keeping weight in a healthier range.Also, for example, weight management for an individual who is overweightor obese can include losing body fat or circumference around the waistwith or without the loss of body weight.

Maintenance of weight loss (weight maintenance) includes preventing,reducing or controlling weight gain after weight loss. It is well knownthat weight gain often occurs after weight loss. Weight loss can occur,for example, from dieting, exercising, illness, drug treatment, surgeryor any combination of these methods, but often an individual that haslost weight will regain some or all of the lost weight Therefore, weightmaintenance in an individual who has lost weight can include preventingweight gain after weight loss, reducing the amount of weigh gained afterweight loss, controlling weight gain after weight loss or slowing therate of weight gain after weight loss.

As used herein, an “individual” is a human. An individual can be anadult or prepubertal (a child) and can be of any gender. The individualcan be a patient or other individual seeking treatment. The methodsdisclosed herein can also apply to non-human mammals such as livestockor pets.

As used herein, “weight management in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from weight management treatment.This judgment is made based on a variety of factors that are in therealm of a healthcare practitioner's expertise, but that includes theknowledge that the individual has a condition that is treatable by themethods disclosed herein.

A healthcare practitioner can include, for example, a physician, nurse,nurse practitioner or other related health care professional who canprescribe or administer compounds (drugs) for weight management,decreasing food intake, inducing satiety, and treating or preventingobesity. In addition, a healthcare practitioner can include anyone whocan recommend, prescribe, administer or prevent an individual fromreceiving a compound or drug including, for example, an insuranceprovider.

In some embodiments, an individual in need of weight management is anindividual who is overweight. In some embodiments, an individual in needof weight management is an individual who has excess visceral adiposity.In some embodiments, an individual in need of weight management is anindividual who is obese. To determine whether an individual isoverweight or obese one can determine a body weight, a body mass index(BMI), a waist circumference or a body fat percentage of the individualto determine if the individual meets a body weight threshold, a BMIthreshold, a waist circumference threshold or a body fat percentagethreshold.

Determination of body weight can be through the use of a visualestimation of body weight, the use of a weight measuring device, such asan electronic weight scale or a mechanical beam scale. In someembodiments, an individual in need of weight management is an adult malewith a body weight greater than about 90 kg, greater than about 100 kg,or greater than about 110 kg. In some embodiments, an individual in needof weight management is an adult female with a body weight greater thanabout 80 kg, greater than about 90 kg, or greater than about 100 kg. Insome embodiments, the individual is prepubertal and has a body weightgreater than about 30 kg, greater than about 40 kg, or greater thanabout 50 kg.

Whether an individual is overweight or obese can be determined on thebasis of their body mass index (BMI) which is calculated by dividingbody weight (kg) by height squared (m²). Thus, the units of BMI arekg/m² and it is possible to calculate the BMI range associated withminimum mortality in each decade of life. According to theclassification from the World Health Organization (W.H.O.), overweightis defined as a BMI in the range 25-30 kg/m², and obesity as a BMIgreater than 30 kg/m² (see below for a detailed W.H.O. BMIclassification).

The International Classification of adult underweight, overweight andobesity according to BMI (World Health Organization) BMI(kg/m2)Principal cut-off Additional cut-off Classification points pointsUnderweight  <18.50  <18.50 Severe thinness  <16.00  <16.00 Moderatethinness 16.00-16.99 16.00-16.99 Mild thinness 17.00-18.49 17.00-18.49Normal range 18.50-24.99 18.50-22.99 23.00-24.99 Overweight ≧25.00≧25.00 Pre-obese 25.00-29.99 25.00-27.49 27.50-29.99 Obese ≧30.00 ≧30.00Obese class I 30.00-34-99 30.00-32.49 32.50-34.99 Obese class II35.00-39.99 35.00-37.49 37.50-39.99 Obese class III ≧40.00 ≧40.00Source: Adapted from WHO, 1995, WHO, 2000 and WHO 2004.

The healthy range of BMI, and other measures of whether one isoverweight or obese, can also be dependent on genetic or racialdifferences. For example, since Asian populations develop negativehealth consequences at a lower BMI than Caucasians, some nations haveredefined obesity for their populations. For example, in Japan any BMIgreater than 25 is defined as obese and in China any BMI greater than 28is defined as obese. Similarly, different threshold values for bodyweight, waist circumference or body fat percentage can be used fordifferent populations of individuals. The additional cut-off pointsincluded in the table above (for example, 23, 27.5, 32.5 and 37.5) wereadded as points for public health action. The WHO recommends thatcountries should use all categories for reporting purposes with a viewto facilitating international comparisons.

Determination of BMI can be through the use of a visual estimation ofBMI, the use of a height measuring device such as a stadiometer or aheight rod and the use of a weight measuring device, such as anelectronic weight scale or a mechanical beam scale. In some embodiments,the individual in need of weight management is an adult with a BMI ofgreater than about 25 kg/m², greater than about 26 kg/m², greater thanabout 27 kg/m², greater than about 28 kg/m², greater than about 29kg/m², greater than about 30 kg/m, greater than about 31 kg/m², greaterthan about 32 d kg/m², greater than about 33 kg/m², greater than about34 kg/m², greater than about 35 kg/m², greater than about 36 kg/m²,greater than about 37 kg/m², greater than about 38 kg/m², greater thanabout 39 kg/m², or greater than about 40 kg/m². In some embodiments, theindividual is prepubertal with a BMI of greater than about 20 kg/m²,greater than about 21 kg/m², greater than about 22 kg/m², greater thanabout 23 kg/m², greater than about 24 kg/m², greater than about 25kg/m², greater than about 26 kg/m², greater than about 27 kg/m², greaterthan about 28 kg/m², greater than about 29 kg/m², greater than about 30kg/m², greater than about 31 kg/m², greater than about 32 kg/m², greaterthan about 33 kg/m², greater than about 34 kg/m², or greater than about35 kg/m².

Determination of waist circumference can be through the use of a visualestimation of waist circumference or the use of a waist circumferencemeasuring device such as a tape measure.

Determinations of the healthy range of waist circumference andpercentage body fat in an individual are dependent on gender. Forexample, women typically have smaller waist circumferences than men andso the waist circumference threshold for being overweight or obese islower for a woman. In addition, women typically have a greaterpercentage of body fat than men and so the percentage body fat thresholdfor being overweight or obese for a woman is higher than for a man.Further, the healthy range of BMI and other measures of whether one isoverweight or obese can be dependent on age. For example, the bodyweight threshold for considering whether one is overweight or obese islower for a child (prepubertal individual) than an adult.

In some embodiments, the individual in need of weight management is anadult male with a waist circumference of greater than about 100 cm,greater than about 110 cm, greater than about 120 cm, greater than about110 cm or an adult female with a waist circumference of greater thanabout 80 cm, greater than about 90 cm, or greater than about 100 cm. Insome embodiments, the individual is prepubertal with a waistcircumference of about of greater than about 60 cm, greater than about70 cm, or greater than about 80 cm.

Determination of body fat percentage can be through the use of a visualestimation of body fat percentage or the use of a body fat percentagemeasuring device such as bioelectric impedance, computed tomography,magnetic resonance imaging, near infrared interactance, dual energy Xray absorptiometry, use of ultrasonic waves, use of body average densitymeasurement, use of skinfold methods, or use of height and circumferencemethods. In some embodiments, the individual in need of weightmanagement is an adult male with a body fat percentage of greater thanabout 25%, greater than about 30%, or greater than about 35% or an adultfemale with a body fat percentage of greater than about 30%, greaterthan about 35%, or greater than about 40%. In some embodiments, theindividual is prepubertal with a body fat percentage of greater thanabout 30%, greater than about 35%, or greater than about 40%.

As used herein, the term “level of renal sufficiency” means the level ofrenal (kidney) function in an individual. As used herein, the levels ofrenal sufficiency in an individual include: no renal impairment, mildrenal impairment, moderate renal impairment, severe renal impairment andend stage renal disease (ESRD). The term renal impairment includes mildrenal impairment, moderate renal impairment, severe renal impairment andend stage renal disease (ESRD).

As disclosed herein, and known to one skilled in the art, there areseveral methods for determining the level of renal sufficiency in anindividual. For example, the level of renal sufficiency in an individualcan be determined by review of past testing done on the individual (i.e.the individual's renal sufficiency has previously been determined). Insome embodiments, a health care practitioner determines the level ofrenal sufficiency of the individual by reading a report. A report canbe, for example, a form or questionnaire that the individual or theirrepresentative fills out, a medical chart for the individual, a medicalrecord for the individual or a laboratory report for the individual.Several tests to determine the level of renal sufficiency in anindividual are known in the art and described herein. In someembodiments, a health care practitioner asks the individual their levelof renal sufficiency (i.e. the individual self-reports their level ofrenal sufficiency).

The level of renal sufficiency in an individual can also be determinedfor the first time when the individual visits the health carepractitioner. In some embodiments, an individual is asked orally or inwriting a series of questions to determine the individual's level ofrenal sufficiency. Questions can include asking about risk factors thatare related to renal sufficiency. Risk factors relevant to anindividual's level of renal sufficiency include, for example, does theindividual have diabetes, high blood pressure, gout, coronary arterydisease, congestive heart failure, severe liver disease or a history ofkidney surgery. Other risk factors associated with renal impairment thatcan be included are, for example, advanced age (for example, 60 yearsold or older), being male, use of a nephrotoxic drug such as furosemide,chemotherapy or HIV infection, protein in the urine, or a solitarykidney.

In some embodiments, an individual is given a test to determine thelevel of renal sufficiency of the individual. For example, a health carepractitioner can order urinalysis or a blood panel for the individual.Urinalysis can include, for example, timed urine collection or a 24 hoururine collection. Urine can be analyzed for the level of protein,glucose, ketones or abnormal debris called casts or the level ofspecific markers such as creatinine can be determined. A blood panel canbe analyzed for markers such as creatinine, blood urea nitrogen (BUN),and electrolytes, for example.

In some embodiments a glomerular filtration rate (GFR) or estimated GFRis determined for the individual to determine the level of renalsufficiency for the individual. GFR is currently considered to be anexcellent overall index of renal function (see Lameire et al., Am J. ofCardiology 98:21K-26K (2006) and references therein). GFR can be definedas the volume of plasma cleared of an ideal substance per unit of time(usually expressed as mL/min). The GFR can be determined by measuringthe renal excretion of a suitable marker such as inulin that is freelyfiltered at the glomerulus and not reabsorbed or secreted in the tubule.Standard inulin clearance requires an intravenous priming dose ofinulin, followed by a constant infusion to establish a steady-stateinulin plasma concentration. After an equilibration for about 45minutes, serial urine samples are collected every 10-20 minutes throughan indwelling bladder catheter or urine is obtained voluntarily every20-30 minutes from an individual who is not catheterized. In practice,determination of GFR using inulin can be difficult since the collectionof timed urine in individuals is inexact and there are often technicaldifficulties encountered in performing inulin infusion and reaching asteady state of inulin distribution (see Schwartz and Furth, PediatrNephrol 22:1839-1848 (2007) and references therein).

Because of difficulties with administering and measuring inulin,standard endogenous creatinine clearances have been used to estimateGFR. Creatinine results from the enzymatic degradation of creatinesynthesized in skeletal muscle. Urinary excretion of creatinine istherefore a product of muscle catabolism and hence an index of musclemass. Creatinine is eliminated exclusively by the kidneys via glomerularfiltration and, to a lesser extent, by tubular secretion. Endogenouscreatinine clearance can provide an acceptable measurement for GFR forclinical purposes. Creatinine clearance is often normalized to bodysurface area (BSA) by being multiplied by the factor 1.73/BSA in squaremeters. Creatinine clearance protocols require simplified urinecollections; however, difficulties with collecting urine have led toprotocols for estimating GFR from serum creatinine. Several formulas areused to estimate GFR including, for example, the Cockcroft-Gaultequation and the Modification of Diet in Renal Disease (MDRD) formulas.In some embodiments, GFR is estimated using serum creatinine levels.

The Cockcroft-Gault equation estimates creatinine clearance on the basisof serum creatinine level, age, sex and weight (see Traynor et al. BMJ33:733-737 (2006) and references therein). It is based on creatinineexcretion in men with normal renal function with a correction for women.It tends to overestimate renal function at lower levels, particularlywhen obesity or fluid overload is present as the resultant increase inweight does not reflect an increase in muscle mass. As disclosed herein,an individual's ideal or otherwise adjusted body weight can be used inthe Cockcroft-Gault equation or an individual's actual body weight canbe used.

A Cockcroft-Gault equation is:

${{Estimated}\mspace{14mu}{creatinine}\mspace{14mu}{clearance}\mspace{14mu}\left( {Cl}_{Cr} \right)} = {\frac{\left( {140 - {age}} \right) \times {weight} \times 1.2}{SCr} \times \left( {0.85\mspace{14mu}{if}\mspace{14mu}{female}} \right)}$where age is expressed in years, SCr in micromole/L and weight in kg(see Traynor, ibid).

A Cockcroft-Gault equation using ideal body weight (IBW) is:

Female:${{GFR}\mspace{14mu}\left( {{mL}\text{/}\min} \right)} = {0.85 \times \frac{\left( {140 - {age}} \right) \times {ideal}\mspace{14mu}{body}\mspace{14mu}{weight}\mspace{14mu}({kg})}{72 \times {serum}\mspace{14mu}{creatinine}\mspace{14mu}\left( {{mg}\text{/}{dL}} \right)}}$Male:${{GFR}\mspace{14mu}\left( {{mL}\text{/}\min} \right)} = \frac{\left( {140 - {age}} \right) \times {ideal}\mspace{14mu}{body}\mspace{14mu}{weight}\mspace{14mu}({kg})}{72 \times {serum}\mspace{14mu}{creatinine}\mspace{14mu}\left( {{mg}\text{/}{dL}} \right)}$Estimate Ideal Body Weight (IBW) in kgFemales: IBW=45.5 kg+2.3 kg for each inch over 5 feetMales: IBW=50 kg+2.3 kg for each inch over 5 feet

A formula derived from data on individuals with advanced renal failurein the Modification of Diet in Renal Disease Study is referred to as the6-variable MDRD. This formula gives an estimate of glomerular filtrationrate in mL/min adjusted for body surface area of 1.73 m² and is based onan individual's age, sex, race and levels of serum urea, serumcreatinine and serum albumin. For example, different numbers are used ifan individual is black or part of the African American race. Asimplified version of the formula using only an individual's age, sex,race, and serum creatinine level is referred to as the 4-variable MDRD.

A 6-variable MDRD is:

170×(S_(Cr)/88.4)^(−0.999)×age^(−0.176)×(SU/0.357)^(−0.170)×(SAlb×10)^(+0.318)×(0.762if female)×(1.80 if black) where S_(Cr)=serum creatinine in micromole/L,sU=serum urea in millimol/L, SAlb=serum albumin in g/L, and age isexpressed in years (sec Traynor, ibid)

A 4-variable MDRD is:

186.3×(S_(Cr)/88.4)^(−1.154)×age^(−0.203)×(0.742 if female)×(1.21 ifblack) where S_(Cr)=serum creatinine in micromole/L and age is expressedin years (see Traynor, ibid)

A modified 4-variable MDRD (traceable by isotope dilution massspectrometry) is:

F×175×(S_(Cr)/88.4)^(−1.154)×age^(−0.203)×(0.742 if female)×(1.21 ifblack)

where F=correction factor, S_(Cr)=serum creatinine in micromole/L andage is expressed in years (see Traynor, ibid)

In addition to measurement of creatinine, protocols exist for estimatingGFR using cystatin C. Because cystatin C is metabolized and not excretedit cannot be used to measure GFR by standard urinary clearancetechniques, but is measured instead from the blood.

Another method for determining GFR is to use a single injectionclearance technique. The renal clearance of a substance that is notmetabolically produced or degraded, and that is excreted from the bodycompletely or almost completely in the urine, can be calculated fromcompartmental analysis by monitoring its rate of disappearance from theplasma following a single intravenous injection. Radioactive markersused for single injection clearance techniques include, for example,¹²⁵I-iothalamate, chromium ethylenediamine tetracetic acid (⁵¹Cr-EDTA),or diethylenetriamine pentacetic acid (^(99m)Tc-DTPA). An alternative tothe use of radioactivity is the use of a radiocontrast agent such asiohexol. Iohexol is a non-ionic, low osmolar, X-ray contract medium(Omnipaque; Amersham Health, NJ) that is eliminated from plasmaexclusively by glomerular filtration. Both urinary clearance of iohexoland plasma disappearance of iohexol methods can be used to determineGFR.

As understood by one skilled in the art, other methods of determiningthe level of renal sufficiency of the individual are possible. Forexample, other formulas for estimating GFR are known in the art such asthe Salazar-Corcoran equation. Also, for example, an absolute,non-corrected GFR can be used (Delanaye et al., Nephrol. Dial.Transplant (2005) 20:2024-2028). In addition, clearance of othercompounds such as urea, urate, low molecular weight proteins such asbeta 2 microglobulin, alpha 1 microglobulin and retinol binding proteinare known in the art.

In some embodiments, GFR is determined using inulin clearance. In someembodiments, GFR is determined using creatinine clearance. In someembodiments, GFR is estimated using serum creatinine levels. In someembodiments, GFR is estimated using the Cockcroft-Gault equation. Insome embodiments, the individual's actual body weight is used in theCockcroft-Gault equation. In some embodiments, an adjusted body weightfor the individual is used in the Cockcroft-Gault equation. In someembodiments, the individual's ideal body weight is used in theCockcroft-Gault equation. In some embodiments, GFR is estimated usingthe Modification of Diet in Renal Disease (MDRD) formula. In someembodiments, GFR is estimated using the 6-variable Modification of Dietin Renal Disease (MDRD) formula. In some embodiments, GFR is estimatedusing the 4-variable Modification of Diet in Renal Disease (MDRD)formula. In some embodiments, GFR is estimated using cystatin C. In someembodiments GFR is determined using a single injection clearancetechnique. In some embodiments, GFR is determined using a radioactivemarker. In some embodiments, GFR is determined using ¹²⁵I-iothalamate,chromium ethylenediamine tetracetic acid (⁵¹Cr-EDTA), ordiethylenetriamine pentacetic acid (^(99m)Tc-DTPA). In some embodiments,GFR is determined using a radiocontrast agent. In some embodiments, GFRis determined using iohexol.

Accordingly, in some embodiments, the level of renal sufficiency in anindividual is determined using inulin clearance. In some embodiments,the level of renal sufficiency in an individual is determined usingcreatinine clearance. In some embodiments, the level of renalsufficiency in an individual is estimated using serum creatinine levels.In some embodiments, the level of renal sufficiency in an individual isestimated using the Cockcroft-Gault equation. In some embodiments, theindividual's actual body weight is used in the Cockcroft-Gault equation.In some embodiments, an adjusted body weight for the individual is usedin the Cockcroft-Gault equation. In some embodiments, the individual'sideal body weight is used in the Cockcroft-Gault equation. In someembodiments, the level of renal sufficiency in an individual isestimated using the Modification of Diet in Renal Disease (MDRD)formula. In some embodiments, the level of renal sufficiency in anindividual is estimated using the 6-variable Modification of Diet inRenal Disease (MDRD) formula. In some embodiments, the level of renalsufficiency in an individual is estimated using the 4-variableModification of Diet in Renal Disease (MDRD) formula. In someembodiments, the level of renal sufficiency in an individual isestimated using cystatin C. In some embodiments the level of renalsufficiency in an individual is determined using a single injectionclearance technique. In some embodiments, the level of renal sufficiencyin an individual is determined using a radioactive marker. In someembodiments, the level of renal sufficiency in an individual isdetermined using ¹²⁵I-iothalamate, chromium ethylenediamine tetraceticacid (⁵¹Cr-EDTA), or diethylenetriamine pentacetic acid (^(99m)Tc-DTPA).In some embodiments, the level of renal sufficiency in an individual isdetermined using a radiocontrast agent. In some embodiments, the levelof renal sufficiency in an individual is determined using iohexol.

As used herein, “no renal impairment” means the individual has normalrenal function. Levels of renal function, renal sufficiency or renalimpairment can be determined using any of the methods known in the artor described herein. Regarding terms such as “mild renal impairment”,“moderate renal impairment”, “severe renal impairment” and “end stagerenal disease (ESRD)” cut-offs to define these levels of renalsufficiency are dependent on the test done to determine the level ofrenal sufficiency.

Different thresholds or cut-offs can be used to determine the level ofrenal sufficiency in an individual depending on the technique used andthe interpretation of the health care practitioner. Several variablescan be considered when determining the level of renal sufficiency in anindividual including, for example, whether an individual is obese, theindividual's race, the individual's gender, and the individual's age.Recommendations regarding classification of renal sufficiency are knownin the art. These recommendations may change over time as newertechniques or better equations are used to more accurately determinerenal function in an individual.

Currently, one common method for determining the level of renalsufficiency in an individual is determining creatinine clearance(Cl_(Cr)) in the individual using of the Cockcroft-Gault equation. Asdisclosed herein, the individual's actual body weight, ideal bodyweight, or otherwise adjusted body weight can be used in the equation.In some embodiments, the following are criteria for determining thelevel of renal sufficiency using creatinine clearance (Cl_(Cr)) and theCockcroft-Gault equation:Normal>80 mL/min

Mild renal impairment=51-80 mL/min

Moderate renal impairment=31-50 mL/min

Severe renal impairment=5-30 mL/min or ≦30 mL/min

End stage renal disease (ESRD) are those requiring dialysis

Another method for determining the level of renal sufficiency in anindividual is to determine an approximate serum creatinine (mg/dL)concentration for the individual. In some embodiments, a way to identifyindividuals with severe renal impairment (or ESRD) is to determineapproximate serum creatinine (mg/dL) and use the following criteria toidentify the individual as having severe renal impairment (or ESRD):

Approximate Serum Creatinine (mg/dL) Age Range Men Women 18-20 >4.9 >3.521-30 >4.5 >3.2 31-40 >4.1 >2.9 41-50 >3.7 >2.7 51-60 >3.3 >2.4 >60 >3.0>2.0

As used herein, “prescribing” means to order, authorize or recommend theuse of a drug or other therapy, remedy or treatment. In someembodiments, a health care practitioner can orally advise, recommend orauthorize the use of a compound, dosage regimen or other treatment to anindividual. In this case the health care practitioner may or may notprovide a prescription for the compound, dosage regimen or treatment.Further the health care practitioner may or may not provide therecommended compound or treatment. For example, the health carepractitioner can advise the individual where to obtain the compoundwithout providing the compound. In some embodiments, a health carepractitioner can provide a prescription for the compound, dosage regimenor treatment to the individual. For example, a health care practitionercan give a written or oral prescription to an individual. A prescriptioncan be written on paper or on electronic media such as a computer file,for example, on a hand held computer device. For example, a health carepractitioner can transform a piece of paper or electronic media with aprescription for a compound, dosage regimen or treatment. In addition, aprescription can be called in (oral) or faxed in (written) to a pharmacyor a dispensary. In some embodiments, a sample of the compound ortreatment can be given to the individual. As used herein, giving asample of a compound constitutes an implicit prescription for thecompound. Different health care systems around the world use differentmethods for prescribing and administering compounds or treatments andthese methods are encompassed by the disclosure.

A prescription can include, for example, an individual's name and/oridentifying information such as date of birth. In addition, for example,a prescription can include, the medication name, medication strength,dose, frequency of administration, route of administration, number oramount to be dispensed, number of refills, physician name, physiciansignature. Further, for example, a prescription can include a DEA numberor state number.

As used herein, “administering” means to provide a compound or othertherapy, remedy or treatment. For example, a health care practitionercan directly provide a compound to an individual in the form of asample, or can indirectly provide a compound to an individual byproviding an oral or written prescription for the compound. Also, forexample, an individual can obtain a compound by themselves without theinvolvement of a health care practitioner.

Administration of the compound may or may not involve the individualactually internalizing the compound. In the case where an individualinternalizes the compound the body is transformed by the compound insome way.

In some embodiments, a health care provider administers Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof to anindividual in the form of a sample.

The disclosure provides a method for weight management in an individualin need thereof, comprising prescribing or administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

The disclosure also provides a method for weight management in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Inaddition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. In someembodiments, the individual has mild renal impairment, moderate renalimpairment, severe renal impairment or ESRD. In some embodiments, theindividual has moderate renal impairment, severe renal impairment orESRD. In some embodiments, the individual has severe renal impairment orESRD. In some embodiments, the individual has ESRD.

A “reduced dosage regimen” as used herein means a reduction in theamount of a compound such as Compound 1 or a pharmaceutically acceptablesalt, solvate or hydrate thereof that an individual is prescribed oradministered in a fixed time period compared to the recommended dosageregimen. In some embodiments, the reduction in the amount of a compoundthat an individual is administered in a fixed time period compared tothe recommended dosage is accomplished by reducing the amount ofCompound 1 in each unit dose. For example, one recommended dosageregimen for Compound 1 or a pharmaceutically acceptable salt, solvate orhydrate thereof is a 10 mg capsule taken twice a day. A reduced dosageregimen can be a capsule (unit dose) with less than 10 mg taken twice aday, for example, a capsule with 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3mg, 2 mg, 1 mg or less than 1 mg taken twice a day. A capsule (unitdose) with less than 10 mg is an example of a low dosage formulation. Insome embodiments, the reduction in the amount of a compound that anindividual is administered in a fixed time period compared to therecommended dosage is accomplished by increasing the time intervalbetween doses. For example, a 10 mg capsule can be administered once perday instead of twice per day to effectively reduce the dose. Inaddition, both a decrease in the amount of compound per unit dose and anincrease the time interval between doses can be used. Since dosing canbe dependent on body weight, it may be that a recommended dosage regimenis expressed in mg of compound per kg of body weight instead of a fixedamount of compound for all individuals. A reduction in the mg ofcompound per kg of body weight is an example of a reduced dosageregimen. Any embodiment that employs a reduced dosage regimen canequally employ a low dosage formulation.

Formulations, such as a low dosage formulation, can be prepared by anysuitable method, typically by uniformly mixing the active compound(s)with liquids or finely divided solid carriers, or both, in the requiredproportions and then, if necessary, forming the resulting mixture into adesired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants can be used intablets and capsules for oral administration. Liquid preparations fororal administration can be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations canbe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants can be added to theliquid preparations. Parenteral dosage forms can be prepared bydissolving the compound in a suitable liquid vehicle and filtersterilizing the solution before filling and sealing an appropriate vialor ampule. These are just a few examples of the many appropriate methodswell known in the art for preparing dosage forms. Suitablepharmaceutically-acceptable carriers, outside those mentioned herein,are known in the art; for example, see Remington, The Science andPractice of Pharmacy, 20^(th) Edition, 2000, Lippincott Williams &Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, acompound can, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds provided herein, together with a conventional adjuvant,carrier, or diluent, can thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof can comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition can be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

The dose when using the compounds provided herein can vary within widelimits and as is customary and is known to the physician, it is to betailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxisconducted or on whether further active compounds are administered inaddition to the compounds provided herein. Representative doses include,but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mgto about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mgto about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may beadministered during the day, especially when relatively large amountsare deemed to be needed, for example 2, 3 or 4 doses. Depending on theindividual and as deemed appropriate from the patient's physician orcaregiver it may be necessary to deviate upward or downward from thedoses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis conductedor on whether further active compounds are administered in addition tothe compounds provided herein and as part of a drug combination. Thedosage regimen for treating a disease condition with the compoundsand/or compositions provided herein is selected in accordance with avariety factors as cited above. Thus, the actual dosage regimen employedmay vary widely and therefore may deviate from a preferred dosageregimen and one skilled in the art will recognize that dosage and dosageregimen outside these typical ranges can be tested and, whereappropriate, may be used in the methods disclosed herein.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day.

The sub-dose itself may be further divided, e.g., into a number ofdiscrete loosely spaced administrations. The daily dose can be divided,especially when relatively large amounts are administered as deemedappropriate, into several, for example 2, 3 or 4 part administrations.If appropriate, depending on individual behavior, it may be necessary todeviate upward or downward from the daily dose indicated.

The compounds provided herein can be administrated in a wide variety oforal and parenteral dosage forms. It will be obvious to those skilled inthe art that the following dosage forms may comprise, as the activecomponent, either a compound provided herein or a pharmaceuticallyacceptable salt, solvate or hydrate of a compound provided herein.

Some embodiments include a method of producing a pharmaceuticalcomposition for “combination-therapy” comprising admixing at least onecompound according to any of the compound embodiments disclosed herein,together with at least one known pharmaceutical agent as describedherein and a pharmaceutically acceptable carrier.

Disclosed herein is a method for weight management in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In any aspect or embodiment where the following language is used “anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 ms/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old” this is        interpreted as being identical to: “a serum creatinine        concentration of:    -   (i) less than about 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than about 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than about 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than about 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than about 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than about 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than about 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than about 3.3 mg/dL for a 51-60 year old man,    -   (x) less than about 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than about 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than about 2.0 mg/dL for a woman over 60 years old.

Similarly, in any aspect or embodiment where the following language isused “an approximate serum creatinine concentration of:

-   -   (i) more than 4.9 mg/dL for an 18-20 year old man,    -   (ii) more than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) more than 4.5 mg/dL for a 21-30 year old man,    -   (iv) more than 3.2 mg/dL for a 21-30 year old woman,    -   (v) more than 4.1 mg/dL for a 31-40 year old man,    -   (vi) more than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) more than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) more than 3.3 mg/dL for a 51-60 year old man,    -   (x) more than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) more than 3.0 mg/dL for a man over 60 years old, or    -   (xii) more than 2.0 mg/dL for a woman over 60 years old this is        interpreted as being identical to: “a serum creatinine        concentration of:    -   (i) more than about 4.9 mg/dL for an 18-20 year old man,    -   (ii) more than about 3.5 mg/dL for an 18-20 year old woman,    -   (iii) more than about 4.5 mg/dL for a 21-30 year old man,    -   (iv) more than about 3.2 mg/dL for a 21-30 year old woman,    -   (v) more than about 4.1 mg/dL for a 31-40 year old man,    -   (vi) more than about 2.9 mg/dL for a 31-40 year old woman,    -   (viii) more than about 2.7 mg/dL for a 41-50 year old woman,    -   (ix) more than about 3.3 mg/dL for a 51-60 year old man,    -   (x) more than about 2.4 mg/dL for a 51-60 year old woman,    -   (xi) more than about 3.0 mg/dL for a man over 60 years old, or    -   (xii) more than about 2.0 mg/dL for a woman over 60 years old.”

Also disclosed herein is a method for weight management in an individualin need thereof, comprising a) determining an approximate serumcreatinine concentration for the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for weight management in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed is a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.

As used herein, the term “greater than” is used interchangeable with thesymbol > and the term less than is used interchangeable with the symbol<. Likewise the term less than or equal to is interchangeable with thesymbol ≦.

When an integer is used in a method disclosed herein, the term “about”can be inserted before the integer. For example, the term “greater than80 mL/minute” can be substituted with “greater than about 80 mL/minute”.

Disclosed herein is a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for weight management in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for weight management in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.

Generally, disclosed herein are methods for reducing the risk of anadverse event in an individual in need of treatment for an indication,comprising determining the level of renal sufficiency of the individualand prescribing or administering a compound such as Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual. Several indications are encompassed as well as severaldifferent methods of determining the level of renal sufficiency of theindividual, and different remedies are prescribed or administered to theindividual. As disclosed above, certain features of the methods, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the methods, which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Regarding indications, the disclosure encompasses a method for weightmanagement in an individual in need thereof, decreasing food intake inan individual, inducing satiety in an individual, for the treatment ofobesity, and the prevention of obesity. In addition, the disclosureencompasses a method of weight loss in an individual or method formaintenance of weight loss in an individual. Further, the disclosureencompasses a method of treating an individual in need of treatment withCompound 1 or a pharmaceutically acceptable salt, solvate or hydratethereof, and of treating a disorder related to 5-HT_(2C) receptoractivity. Any of these indications can be combined with any of themethods of determining the level of renal sufficiency in an individual,and any remedy prescribed or administered to the individual unlessspecifically stated otherwise or the context requires otherwise.

Regarding the methods of determining the level of renal sufficiency inan individual, in some embodiments the level of renal sufficiency isdetermined by the Cockcroft-Gault equation which can be calculated usingthe individual's actual, ideal or otherwise adjusted body weight. Inother embodiments the level of renal sufficiency is determined bycalculating the glomerular filtration rate (GFR) of the individual byone of many methods known in the art such as using a radioactivelylabeled marker. The GFR can also be estimated using the Cockcroft-Gaultequation or the modification of diet in renal disease (MDRD) formula,usually calculated with 4 or 6 variables. The serum creatinineconcentration of the individual can also be used to determine the levelof renal sufficiency of an individual. In some embodiments, the methodof determining the level of renal sufficiency in the individual is notspecified. In some embodiments the individual is asked about their levelof renal sufficiency either orally or on a form.

The levels of renal sufficiency of an individual can include, forexample, no renal impairment (i.e., normal renal function), mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD.In some embodiments, the level of renal sufficiency is not specified.The methods disclosed herein can comprise prescribing or administeringdifferent remedies such as Compound 1 or a pharmaceutically acceptablesalt, solvate or hydrate thereof, Compound 1 hydrochloride and hydratesthereof, Compound 1 hydrochloride hemihydrate or Compound 1hydrochloride hemihydrate, Form III. The method can also compriseprescribing or administering a reduced dosage regimen of Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof, or ananti-obesity drug other than Compound 1 or a pharmaceutically acceptablesalt, solvate or hydrate thereof, or a reduced-calorie diet and/orregular exercise program.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Also disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of weight management, comprising: a) determining thelevel of renal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

As used herein, an “adverse event” or “toxic event” is any untowardmedical occurrence that may present itself during treatment. Adverseevents associated with treatment with Compound 1 or a pharmaceuticallyacceptable salt, solvate or hydrate thereof are disclosed herein, forexample, in Example 6 and Table 11. Possible adverse events disclosed inExample 6 include, abdominal pain, diarrhea, dyspepsia, stomachdiscomfort, and worsening renal impairment, dizziness, headache. Otherpossible adverse events based on observations from studies in monkeysinclude emesis, decreased food intake, weight loss, decreased activity,spontaneous penile erection, tremors or seizures. Additional possibleadverse events include, for example, nausea, blurred vision,paresthesias, dry mouth and fatigue. In the methods disclosed herein,the term adverse event can be replaced by other more general terms suchas toxicity. The term “reducing the risk” of an adverse event meansreducing the probability that an adverse event or toxic event couldoccur.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of weight management, comprisingprescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Alsodisclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a)determining the level of renal sufficiency of the individual, and b)administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Further disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of weight management, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of weight management, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Generally, disclosed herein are methods for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof,comprising determining the level of renal sufficiency of the individualand selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof based onthe individual's renal sufficiency.

Regarding the methods of determining the level of renal sufficiency inan individual, in some embodiments the level of renal sufficiency isdetermined by the Cockcroft-Gault equation which can be calculated usingthe individual's actual, ideal or otherwise adjusted body weight. Inother embodiments the level of renal sufficiency is determined bycalculating the glomerular filtration rate (GFR) of the individual byone of many methods known in the art such as using a radioactivelylabeled marker. The GFR can also be estimated using the Cockcroft-Gaultequation or the modification of diet in renal disease (MDRD) formula,usually calculated with 4 or 6 variables. The serum creatinineconcentration of the individual can also be used to determine the levelof renal sufficiency of an individual. In some embodiments, the methodof determining the level of renal sufficiency in the individual is notspecified. In some embodiments the individual is asked about their levelof renal sufficiency either orally or on a form.

The levels of renal sufficiency of an individual can include, forexample, no renal impairment (i.e., normal renal function), mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD.In some embodiments, the level of renal sufficiency is not specified.The methods disclosed herein can comprise selecting the individual fortreatment with different remedies such as Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof, Compound 1hydrochloride and hydrates thereof, Compound 1 hydrochloride hemihydrateor Compound 1 hydrochloride hemihydrate, Form III. The method can alsocomprise selecting an individual for treatment with a reduced dosageregimen of Compound 1 or a pharmaceutically acceptable salt, solvate orhydrate thereof, or an anti-obesity drug other than Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

As used herein, a “plurality of individuals” means more than oneindividual. For example, a plurality of individuals can be a small orlarge population of individuals. According to the methods disclosedherein, these individuals are screened for treatment with Compound 1 ora pharmaceutically acceptable salt, solvate or hydrate thereof based ontheir level of renal sufficiency.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual does not have severe renal impairment or ESRD.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has renal impairment.

Further disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for selecting an individualfor treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a method for selecting an individual fortreatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-11H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual has a creatinine clearance rate of greater thanabout 80 mL/minute, greater than about 50 mL/minute or greater thanabout 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a compound for use in a method of weight managementin an individual, said method comprising prescribing said compound tosaid individual, wherein said individual has previously been determinedto have a level of renal sufficiency selected from the group consistingof: no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising administering saidcompound to said individual, wherein said individual has previously beendetermined to have a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, disclosed herein is a compound for use in a method ofweight management in an individual, said method comprising prescribing atherapeutically effective amount of said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising administering atherapeutically effective amount of said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising prescribing saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising administering saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising determining thelevel of renal sufficiency of said individual and prescribing saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, moderate renal impairment, severerenal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

In addition, disclosed herein is a compound for use in a method ofweight management in an individual, said method comprising determiningthe level of renal sufficiency of said individual and administering saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, moderate renal impairment, severerenal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

A dosage level appropriate for the level of renal sufficiency of anindividual can be, for example, a dosage level as disclosed throughoutthis application. In some embodiments, a dosage level appropriate forthe level of renal sufficiency is a full dosage regimen. In someembodiments, a dosage level appropriate for the level of renalsufficiency is 10 mg(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, twice aday. In some embodiments, a dosage level appropriate for the level ofrenal sufficiency is a reduced dosage regimen. In some embodiments, alow dosage formulation is a dosage level appropriate for a level ofrenal sufficiency. For example, a low dosage formulation of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof can be anappropriate dosage for an individual with renal impairment. In someembodiments, a dosage level appropriate for the level of renalsufficiency is no dose (i.e. the compound is not prescribed oradministered). For example, the compound would not be prescribed oradministered to an individual with severe renal impairment or ESRD Forexample, disclosed herein is a compound for use in a method of weightmanagement in an individual, said method comprising prescribing oradministering a reduced dosage regimen of said compound; wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of weight managementin an individual having moderate, mild or no renal impairment, saidmethod comprising prescribing said compound to said individual, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment; wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of weightmanagement in an individual having moderate, mild or no renalimpairment, said method comprising administering said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a low dosage formulation of a compound for usein a method of weight management in an individual, said methodcomprising prescribing said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of weight management in an individual, said methodcomprising administering said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of weight management in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of weight management in an individual, wherein said lowdosage prevents a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for weightmanagement, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of Compound 1. Compound 1can be prescribed or administered as an adjunct to diet and exercise forweight management in an individual.

In some embodiments, the weight management comprises weight loss.

In some embodiments, the weight management comprises maintenance ofweight loss.

In some embodiments, the weight management further comprises prescribingor administering a reduced-calorie diet.

In some embodiments, the weight management further comprises prescribingor administering a program of regular exercise.

In some embodiments, the weight management further comprises prescribingor administering both a reduced-calorie diet and a program of regularexercise.

In some embodiments, the individual is a patient with an initial bodymass index ≧30 kg/m².

In some embodiments, the individual is a patient with an initial bodymass index ≧27 kg/m² in the presence of at least one weight relatedcomorbid condition.

In some embodiments, the individual is a patient with an initial bodymass index ≧27 kg/m² in the presence of at least one weight relatedcomorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, the individual has an initial body mass index ≧30kg/m².

In some embodiments, the individual has an initial body mass index ≧27kg/m².

In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid condition.

In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea.

In some embodiments, the individual has an initial body mass index ≧25kg/m².

In some embodiments, the individual has an initial body mass index ≧25kg/m² in the presence of at least one weight related comorbid condition.

In some embodiments, the individual has an initial body mass index ≧25kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea.

In some embodiments, the method for weight management further comprisesprescribing or administering a weight loss compound or procedure inaddition to prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments, the method for weight management further comprisesprescribing or administering phentermine to the individual. In someembodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof isprescribed or administered before or after a surgical weight lossprocedure, for example, a lap band or gastric bypass surgery.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of weight management, comprising administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Further disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of weight management, comprising administering areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has renal impairment.Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of weight management, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein an approximate serum creatinine concentration hasbeen determined for the individual, and provided that the individual hasan approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment. Further disclosed herein is amethod for selecting an individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Also disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. In addition,disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

In addition, disclosed herein is a method for decreasing food intake inan individual in need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD).

Also disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD). In addition, disclosedherein is a method for decreasing food intake in an individual in needthereof, comprising: a) determining the level of renal sufficiency ofthe individual, and b) administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate, Form III.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual.

In some embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in other embodiments the individual'sactual body weight is used in the Cockcroft-Gault equation.

In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

As used herein, “decreasing food intake in an individual in needthereof” refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from decreasing food intake. Thisjudgment is made based on a variety of factors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition, for example, obesity, that istreatable by the methods disclosed herein.

In some embodiments, an individual in need of decreasing food intake isan individual who is overweight. In some embodiments, an individual inneed of decreasing food intake is an individual who is obese.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising prescribing or administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Also disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Inaddition, disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. In someembodiments, the individual has mild renal impairment, moderate renalimpairment, severe renal impairment or ESRD. In some embodiments, theindividual has moderate renal impairment, severe renal impairment orESRD. In some embodiments, the individual has severe renal impairment orESRD. In some embodiments, the individual has ESRD.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising a) determining an approximateserum creatinine concentration for the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for decreasing food intake inan individual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a method for decreasing food intake in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for decreasing food intake inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for decreasing food intake inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for decreasing food intake in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for decreasing food intake inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Also disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of decreasing food intake, comprising: a) determiningthe level of renal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprisingprescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Alsodisclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprising: a)determining the level of renal sufficiency of the individual, and b)administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Further disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprising:a) determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual does not have severe renal impairment or ESRD.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has renal impairment.

Further disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for selecting an individualfor treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprising:a) determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprising

selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual has a creatinine clearance rate of greater thanabout 80 mL/minute, greater than about 50 mL/minute or greater thanabout 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a compound for use in a method of decreasingfood intake in an individual, said method comprising prescribing saidcompound to said individual, wherein said individual has previously beendetermined to have a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofdecreasing food intake in an individual, said method comprisingadministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, disclosed herein is a compound for use in a method ofdecreasing food intake in an individual, said method comprisingprescribing a therapeutically effective amount of said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofdecreasing food intake in an individual, said method comprisingadministering a therapeutically effective amount of said compound tosaid individual, wherein said individual has previously been determinedto have a level of renal sufficiency selected from the group consistingof: no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of decreasing foodintake in an individual, said method comprising prescribing saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a compound for use in a method of decreasing foodintake in an individual, said method comprising administering saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

In addition, disclosed herein is a compound for use in a method ofdecreasing food intake in an individual, said method comprisingdetermining the level of renal sufficiency of said individual andprescribing said compound at a dosage level appropriate for the level ofrenal sufficiency of said individual, wherein said individual has alevel of renal sufficiency selected from the group consisting of: norenal impairment, mild renal impairment, moderate renal impairment,severe renal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Further,disclosed herein is a compound for use in a method of decreasing foodintake in an individual, said method comprising determining the level ofrenal sufficiency of said individual and administering said compound ata dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Forexample, disclosed herein is a compound for use decreasing food intakein an individual, said method comprising prescribing or administering areduced dosage regimen of said compound; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of decreasing foodintake in an individual having moderate, mild or no renal impairment,said method comprising prescribing said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofdecreasing food intake in an individual having moderate, mild or norenal impairment, said method comprising administering said compound tosaid individual, wherein said individual has previously been determinedto have a level of renal sufficiency selected from the group consistingof: no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of decreasing food intake in an individual, said methodcomprising prescribing said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of decreasing food intake in an individual, said methodcomprising administering said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of decreasing food intake in an individual, wherein said lowdosage reduces a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Disclosedherein is a low dosage formulation of a compound for use in a method ofdecreasing food intake in an individual, wherein said low dosageprevents a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for decreasingfood intake, comprising administering to an individual in need thereof,a therapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

In some embodiments, the individual in need of decreasing food intake isa patient with an initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of decreasing food intake isa patient with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition.

In some embodiments, the individual in need of decreasing food, intakeis a patient with an initial body mass index ≧27 kg/m² in the presenceof at least one weight related comorbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intoleranceand sleep apnea.

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧27 kg/m².

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧25 kg/m².

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧25 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of decreasing food intakehas an initial body mass index ≧25 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, decreasing food intake comprises weight loss. Insome embodiments, decreasing food intake comprises maintenance of weightloss. In some embodiments, decreasing food intake further comprises areduced-calorie diet. In some embodiments, decreasing food intakefurther comprises a program of regular exercise. In some embodiments,decreasing food intake further comprises both a reduced-calorie diet anda program of regular exercise.

In some embodiments, the method for decreasing food intake furthercomprises prescribing or administering a weight loss compound orprocedure in addition to prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments, the method for decreasing food intake further comprisesprescribing or administering phentermine to the individual. In someembodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof isprescribed or administered before or after a surgical weight lossprocedure, for example, a lap band or gastric bypass surgery.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Further disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of decreasing food intake, comprising administering areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has renal impairment.Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of decreasing food intake, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein an approximate serum creatinine concentration hasbeen determined for the individual, and provided that the individual hasan approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment. Further disclosed herein is amethod for selecting an individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20-year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Also disclosed herein is a method for inducing satiety in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) prescribing a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. In addition,disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising: a) determining the level of renal sufficiencyof the individual, and b) administering a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

In addition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD).

Also disclosed herein is a method for inducing satiety in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) prescribing therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD). In addition, disclosedherein is a method for inducing satiety in an individual in needthereof, comprising: a) determining the level of renal sufficiency ofthe individual, and b) administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate, Form III.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual.

In some embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in other embodiments the individual'sactual body weight is used in the Cockcroft-Gault equation.

In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

As used herein, “satiety” is the quality or state of being fed orgratified to or beyond capacity. Satiety is a feeling that an individualhas and so it is often determined by asking the individual, orally or inwriting, if they feel full, sated, or satisfied at timed intervalsduring a meal. For example, an individual who feels sated may reportfeeling full, feeling a decreased or absent hunger, feeling a decreasedor absent desire to eat, or feeling a lack of drive to cat. Whilefullness is a physical sensation, satiety is a mental feeling. Anindividual who feels full, sated or satisfied is more likely to stopeating and therefore inducing satiety can result in a decrease in foodintake in an individual.

As used herein, “inducing satiety in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from inducing satiety.

This judgment is made based on a variety of factors that are in therealm of a healthcare practitioner's expertise, but that includes theknowledge that the individual has a condition, for example, obesity,that is treatable by the methods of the disclosure.

In some embodiments, an individual in need of inducing satiety is anindividual who is overweight. In some embodiments, an individual in needof inducing satiety is an individual who is obese.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising prescribing or administering a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Also disclosed herein is a method for inducing satiety in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) prescribing a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Inaddition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. In someembodiments, the individual has mild renal impairment, moderate renalimpairment, severe renal impairment or ESRD. In some embodiments, theindividual has moderate renal impairment, severe renal impairment orESRD. In some embodiments, the individual has severe renal impairment orESRD. In some embodiments, the individual has ESRD.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising a) determining an approximate serum creatinineconcentration for the individual, and b) prescribing a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 ms/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for inducing satiety in an individual inneed thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for inducing satiety in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising: a) determiningthe level of renal sufficiency of the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Disclosed hereinis a method for reducing the risk of an adverse event in an individualin need of inducing satiety, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprisingprescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising: a) determiningthe level of renal sufficiency of the individual, and b) prescribing areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Alsodisclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising: a) determiningthe level of renal sufficiency of the individual, and b) administering areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Further disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising: a) determiningan approximate serum creatinine concentration for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety comprising prescribing oradministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual does not have severe renal impairment or ESRD.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has renal impairment.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for selecting an individualfor treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual has a creatinine clearance rate of greater thanabout 80 mL/minute, greater than about 50 mL/minute or greater thanabout 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a compound for use in a method of inducingsatiety in an individual, said method comprising prescribing saidcompound to said individual, wherein said individual has previously beendetermined to hive a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of inducingsatiety in an individual, said method comprising administering saidcompound to said individual, wherein said individual has previously beendetermined to have a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, disclosed herein is a compound for use in a method ofinducing satiety in an individual, said method comprising prescribing atherapeutically effective amount of said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of inducingsatiety in an individual, said method comprising administering atherapeutically effective amount of said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of inducing satietyin an individual, said method comprising prescribing said compound at adosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, moderate renal impairment,severe renal impairment and ESRD; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of inducingsatiety in an individual, said method comprising administering saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a compound for use in a method of inducingsatiety in an individual, said method comprising determining the levelof renal sufficiency of said individual and prescribing said compound ata dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Further,disclosed herein is a compound for use in a method of inducing satietyin an individual, said method comprising determining the level of renalsufficiency of said individual and administering said compound at adosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, disclosed herein is a compound for use in a method ofinducing satiety in an individual, said method comprising prescribing oradministering a reduced dosage regimen of said compound; wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of inducing satietyin an individual having moderate, mild or no renal impairment, saidmethod comprising prescribing said compound to said individual, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment; wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method of inducingsatiety in an individual having moderate, mild or no renal impairment,said method comprising administering said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a low dosage formulation of a compound for usein a method of inducing satiety in an individual, said method comprisingprescribing said low dosage formulation of the compound to saidindividual, wherein said individual has previously been determined tohave renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of inducing satiety in an individual, said methodcomprising administering said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of inducing satiety in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a low dosage formulation of a compound for use in amethod of inducing satiety in an individual, wherein said low dosageprevents a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for inducingsatiety, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

In some embodiments, the individual in need of inducing satiety is apatient with an initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of inducing satiety is apatient with an initial body mass index ≧27 kg/m² in the presence of atleast one weight related comorbid condition.

In some embodiments, the individual in need of inducing satiety is apatient with an initial body mass index ≧27 kg/m² in the presence of atleast one weight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧30 kg/m².

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧27 kg/m².

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition.

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧25 kg/m².

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧25 kg/m² in the presence of at least one weightrelated comorbid condition.

In some embodiments, the individual in need of inducing satiety has aninitial body mass index ≧25 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, inducing satiety comprises weight loss. In someembodiments, inducing satiety comprises maintenance of weight loss. Insome embodiments, inducing satiety further comprises a reduced-caloriediet. In some embodiments, inducing satiety further comprises a programof regular exercise. In some embodiments, inducing satiety furthercomprises both a reduced-calorie diet and a program of regular exercise.

In some embodiments, the method for inducing satiety further comprisesprescribing or administering a weight loss compound or procedure inaddition to prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments, the method for inducing satiety further comprisesprescribing or administering phentermine to the individual. In someembodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof isprescribed or administered before or after a surgical weight lossprocedure, for example, a lap band or gastric bypass surgery.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Further disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of inducing satiety, comprising administering areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has renal impairment.Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of inducing satiety, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein an approximate serum creatinine concentration hasbeen determined for the individual, and provided that the individual hasan approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment. Further disclosed herein is amethod for selecting an individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Also disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. In addition,disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

In addition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD).

Also disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD). In addition, disclosedherein is a method for treatment of obesity in an individual in needthereof, comprising: a) determining the level of renal sufficiency ofthe individual, and b) administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate, Form III.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual.

In some embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in other embodiments the individual'sactual body weight is used in the Cockcroft-Gault equation.

In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

As used herein the term “treat,” “treating” or “treatment” refers to theadministration of therapy to an individual who already manifests atleast one symptom of a disease or condition or who has previouslymanifested at least one symptom of a disease or condition. For example,“treating” can include alleviating, abating or ameliorating a disease orcondition symptoms, preventing additional symptoms, ameliorating orpreventing the underlying metabolic causes of symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition eitherprophylacticly and/or therapeutically. For example, the term “treating”in reference to a disorder means a reduction in severity of one or moresymptoms associated with a particular disorder. Therefore, treating adisorder does not necessarily mean a reduction in severity of allsymptoms associated with a disorder and does not necessarily mean acomplete reduction in the severity of one or more symptoms associatedwith a disorder. For example, a method for treatment of obesity canresult in weight loss; however, the weight loss does not need to beenough such that the individual is no longer obese. It has been shownthat even modest decreases in weight or related parameters such as BMI,waist circumference and percent body fat, can result in improvement ofhealth, for example, lower blood pressure, improved blood lipidprofiles, or a reduction in sleep apnea.

As used herein, “treatment of obesity in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from treatment of obesity. Thisjudgment is made based on a variety of factors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition that is treatable by the methods ofthe disclosure.

To determine whether an individual is obese one can determine a bodyweight, a body mass index (BMI), a waist circumference or a body fatpercentage of the individual to determine if the individual meets a bodyweight threshold, a BMI threshold, a waist circumference threshold or abody fat percentage threshold.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising prescribing or administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Also disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Inaddition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. In someembodiments, the individual has mild renal impairment, moderate renalimpairment, severe renal impairment or ESRD. In some embodiments, theindividual has moderate renal impairment, severe renal impairment orESRD. In some embodiments, the individual has severe renal impairment orESRD. In some embodiments, the individual has ESRD.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising a) determining an approximateserum creatinine concentration for the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for treatment of obesity in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for treatment of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising prescribingor administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Also disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of treatment of obesity, comprising: a) determiningthe level of renal sufficiency of the individual, and

b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising prescribingor administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprisingprescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Alsodisclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Further disclosed herein a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity comprising prescribingor administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprising: a)determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual does not have severe renal impairment or ESRD.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has renal impairment.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for selecting an individualfor treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual has a creatinine clearance rate of greater thanabout 80 mL/minute, greater than about 50 mL/minute or greater thanabout 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a compound for use in a method of treatment ofobesity in an individual, said method comprising prescribing saidcompound to said individual, wherein said individual has previously beendetermined to have a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method oftreatment of obesity in an individual, said method comprisingadministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, also disclosed herein is a compound for use in a method oftreatment of obesity in an individual, said method comprisingprescribing a therapeutically effective amount of said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method oftreatment of obesity in an individual, said method comprisingadministering a therapeutically effective amount of said compound tosaid individual, wherein said individual has previously been determinedto have a level of renal sufficiency selected from the group consistingof: no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method for treatment ofobesity in an individual, said method comprising prescribing saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method fortreatment of obesity in an individual, said method comprisingadministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a compound for use in a method for treatment ofobesity in an individual, said method comprising determining the levelof renal sufficiency of said individual and prescribing said compound ata dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a compound for use in a method for treatment ofobesity in an individual, said method comprising determining the levelof renal sufficiency of said individual and administering said compoundat a dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method for treatment ofobesity in an individual, said method comprising prescribing oradministering a reduced dosage regimen of said compound, wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of treatment ofobesity in an individual having moderate, mild or no renal impairment,said method comprising prescribing said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method oftreatment of obesity in an individual having moderate, mild or no renalimpairment, said method comprising administering said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a low dosage formulation of a compound for usein a method of treatment of obesity in an individual, said methodcomprising prescribing said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of treatment of obesity in an individual, said methodcomprising administering said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of treatment of obesity in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a low dosage formulation of a compound for use in amethod of treatment of obesity in an individual, wherein said low dosageprevents a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for treatmentof obesity, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

In some embodiments, the treatment of obesity comprises weight loss.

In some embodiments, the treatment of obesity comprises maintenance ofweight loss.

In some embodiments, the treatment of obesity further comprises areduced-calorie diet.

In some embodiments, the treatment of obesity further comprises aprogram of regular exercise.

In some embodiments, the treatment of obesity further comprises both areduced-calorie diet and a program of regular exercise.

In some embodiments, the individual in need of treatment of obesity is apatient with an initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of treatment of obesity isan individual with an initial body mass index ≧27 kg/m² in the presenceof at least one weight related comorbid condition. For example, theindividual can belong to an ethnic group where an initial BMI of ≧27kg/m² is considered obese.

In some embodiments, the individual in need of treatment of obesity isan individual with an initial body mass index ≧27 kg/m² in the presenceof at least one weight related comorbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intoleranceand sleep apnea.

In some embodiments, the individual in need of treatment of obesity hasan initial body mass index ≧30 kg/m².

In some embodiments, the individual in need of treatment of obesity hasan initial body mass index ≧27 kg/m².

In some embodiments, the individual in need of treatment of obesity hasan initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of treatment of obesity hasan initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, the method for treatment of obesity furthercomprises prescribing or administering a weight loss compound orprocedure in addition to prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments, the method for treatment of obesity further comprisesprescribing or administering phentermine to the individual. In someembodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof isprescribed or administered before or after a surgical weight lossprocedure, for example, a lap band or gastric bypass surgery. In someembodiments, the method for the treatment of obesity further comprisesgastric electrical stimulation.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Further disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of treatment of obesity, comprising administering areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein the level of renal sufficiency of the individual hasbeen determined, and provided that the individual has renal impairment.Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of treatment of obesity, comprisingadministering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, wherein an approximate serum creatinine concentration hasbeen determined for the individual, and provided that the individual hasan approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment. Further disclosed herein is amethod for selecting an individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if it isdetermined that the individual has an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Also disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. In addition,disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising: a) determining the level of renalsufficiency of the individual, and b) administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

In addition, disclosed herein is a method for prevention of obesity inan individual in need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD).

Also disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or end stage renal disease (ESRD). In addition, disclosedherein is a method for prevention of obesity in an individual in needthereof, comprising: a) determining the level of renal sufficiency ofthe individual, and b) administering a therapeutically effective amountof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand hydrates thereof.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate, Form III.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual.

In some embodiments, the individual's ideal body weight is used in theCockcroft-Gault equation and in other embodiments the individual'sactual body weight is used in the Cockcroft-Gault equation.

In some embodiments, the individual's serum creatinine concentration isused to determine the level of renal sufficiency of the individual.

As used herein, the term “prevention” such as prevention of obesitymeans prevention of the occurrence or onset of one or more symptomsassociated with a particular disorder and does not necessarily mean thecomplete prevention of a disorder. For example, the term “prevent,”“preventing” and “prevention” refers to the administration of therapy ona prophylactic or preventative basis to an individual who may ultimatelymanifest at least one symptom of a disease or condition but who has notyet done so. Such individuals can be identified on the basis of riskfactors that are known to correlate with the subsequent occurrence ofthe disease. Alternatively, prevention therapy can be administeredwithout prior identification of a risk factor, as a prophylacticmeasure. Delaying the onset of the at least one symptom can also beconsidered prevention or prophylaxis.

As used herein, “prevention of obesity in an individual in need thereof”refers to a judgment made by a healthcare practitioner that anindividual requires or will benefit from prevention of obesity. Thisjudgment is made based on a variety of factors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledgethat the individual has a condition that is treatable by the methodsdisclosed herein.

In some embodiments, an individual in need of prevention of obesity isan individual who is overweight (also called pre-obese). In someembodiments, an individual in need of prevention of obesity is anindividual who has a family history of obesity. To determine whether anindividual is overweight one can determine a body weight, a body massindex (BMI), a waist circumference or a body fat percentage of theindividual to determine if the individual meets a body weight threshold,a BMI threshold, a waist circumference threshold or a body fatpercentage threshold.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising prescribing or administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Also disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) prescribing a reduced dosageregimen of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Inaddition, disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising: a) determining the level ofrenal sufficiency of the individual, and b) administering a reduceddosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. In someembodiments, the individual has mild renal impairment, moderate renalimpairment, severe renal impairment or ESRD. In some embodiments, theindividual has moderate renal impairment, severe renal impairment orESRD. In some embodiments, the individual has severe renal impairment orESRD. In some embodiments, the individual has ESRD.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising a) determining an approximateserum creatinine concentration for the individual, and b) prescribing atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for prevention of obesity inan individual in need thereof, comprising: a) determining an approximateserum creatinine concentration for the individual, and b) administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising prescribing or administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a method for prevention of obesity in anindividual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for prevention of obesity inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for prevention of obesity inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 50 ml/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for prevention of obesity in an individualin need thereof, comprising: a) determining a creatinine clearance rateusing the Cockcroft-Gault equation for the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.In addition, disclosed herein is a method for prevention of obesity inan individual in need thereof, comprising: a) determining a creatinineclearance rate using the Cockcroft-Gault equation for the individual,and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment. Also disclosedherein is a method for reducing the risk of an adverse event in anindividual in need of prevention of obesity, comprising: a) determiningthe level of renal sufficiency of the individual, and b) administering atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual does not have severe renalimpairment or ESRD.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of prevention of obesity, comprisingprescribing or administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)prescribing a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment. Alsodisclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprising: a)determining the level of renal sufficiency of the individual, and b)administering a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has renal impairment.

Further disclosed herein a method for reducing the risk of an adverseevent in an individual in need of prevention of obesity, comprisingprescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) prescribing a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a method for reducing the risk of an adverseevent in an individual in need of prevention of obesity, comprising: a)determining an approximate serum creatinine concentration for theindividual, and b) administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Disclosed herein is a method for reducing the risk of an adverse eventin an individual in need of prevention of obesity comprising prescribingor administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a creatinine clearance rateof greater than about 80 mL/minute, greater than about 50 mL/minute orgreater than about 30 mL/minute using the Cockcroft-Gault equation.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprising:a) determining the level of renal sufficiency of the individual; and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment.

Disclosed herein is a method for selecting an individual for treatmentwith (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual does not have severe renal impairment or ESRD.

Also disclosed herein is a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingselecting the individual for treatment with a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has renal impairment.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a method for selecting an individualfor treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprising:a) determining an approximate serum creatinine concentration for theindividual, and b) selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof if theindividual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein a method for selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingselecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof providedthat the individual has a creatinine clearance rate of greater thanabout 80 mL/minute, greater than about 50 ml/minute or greater thanabout 30 mL/minute using the Cockcroft-Gault equation.

Also disclosed herein is a compound for use in a method of prevention ofobesity in an individual, said method comprising prescribing saidcompound to said individual, wherein said individual has previously beendetermined to have a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofprevention of obesity in an individual, said method comprisingadministering said compound to said individual, wherein said individualhas previously been determined to have a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, and moderate renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

For example, disclosed herein is a compound for use in a method ofprevention of obesity in an individual, said method comprisingprescribing a therapeutically effective amount of said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofprevention of obesity in an individual, said method comprisingadministering a therapeutically effective amount of said compound tosaid individual, wherein said individual has previously been determinedto have a level of renal sufficiency selected from the group consistingof: no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of prevention ofobesity in an individual, said method comprising prescribing saidcompound at a dosage level appropriate for the level of renalsufficiency of said individual, wherein said individual has previouslybeen determined to have a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment,moderate renal impairment, severe renal impairment and ESRD; whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofprevention of obesity in an individual, said method comprisingadministering said compound at a dosage level appropriate for the levelof renal sufficiency of said individual, wherein said individual haspreviously been determined to have a level of renal sufficiency selectedfrom the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a compound for use in a method of prevention ofobesity in an individual, said method comprising determining the levelof renal sufficiency of said individual and prescribing said compound ata dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a compound for use in a method of prevention ofobesity in an individual, said method comprising determining the levelof renal sufficiency of said individual and administering said compoundat a dosage level appropriate for the level of renal sufficiency of saidindividual, wherein said individual has a level of renal sufficiencyselected from the group consisting of: no renal impairment, mild renalimpairment, moderate renal impairment, severe renal impairment and ESRD;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of prevention ofobesity in an individual, said method comprising prescribing oradministering a reduced dosage regimen of said compound, wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a compound for use in a method of prevention ofobesity in an individual having moderate, mild or no renal impairment,said method comprising prescribing said compound to said individual,wherein said individual has previously been determined to have a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a compound for use in a method ofprevention of obesity in an individual having moderate, mild or no renalimpairment, said method comprising administering said compound to saidindividual, wherein said individual has previously been determined tohave a level of renal sufficiency selected from the group consisting of:no renal impairment, mild renal impairment, and moderate renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a low dosage formulation of a compound for usein a method of prevention of obesity in an individual, said methodcomprising prescribing said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a low dosage formulation of a compound foruse in a method of prevention of obesity in an individual, said methodcomprising administering said low dosage formulation of the compound tosaid individual, wherein said individual has previously been determinedto have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Disclosed herein is a low dosage formulation of a compound for use in amethod of prevention of obesity in an individual, wherein said lowdosage reduces a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. A lowdosage formulation of a compound for use in a method of prevention ofobesity in an individual, wherein said low dosage prevents a toxic eventin said individual to said compound, wherein said individual haspreviously been determined to have renal impairment; and wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for preventionof obesity, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

In some embodiments, the prevention of obesity comprises weight loss.

In some embodiments, the prevention of obesity comprises maintenance ofweight loss.

In some embodiments, the prevention of obesity further comprises areduced-calorie diet.

In some embodiments, the prevention of obesity further comprises aprogram of regular exercise.

In some embodiments, the prevention of obesity further comprises both areduced-calorie diet and a program of regular exercise.

In some embodiments, the individual in need of prevention of obesity isa patient with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition.

In some embodiments, the individual in need of prevention of obesity isa patient with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intoleranceand sleep apnea.

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧27 kg/m².

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧25 kg/m².

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧25 kg/m² in the presence of at least oneweight related comorbid condition.

In some embodiments, the individual in need of prevention of obesity hasan initial body mass index ≧25 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea.

In some embodiments, the method for prevention of obesity furthercomprises prescribing or administering a weight loss compound orprocedure in addition to prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. In someembodiments, the method for prevention of obesity further comprisesprescribing or administering phentermine to the individual. In someembodiments, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof isprescribed or administered before or after a surgical weight loss(bariatric) procedure, for example, a lap band or gastric bypasssurgery.

One aspect of the present disclosure pertains to a method for weightmanagement in an individual in need thereof, comprising: a) determiningan approximate serum creatinine concentration for the individual, and b)not prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) more than 4.9 mg/dL for an 18-20 year old man,    -   (ii) more than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) more than 4.5 mg/dL for a 21-30 year old man,    -   (iv) more than 3.2 mg/dL for a 21-30 year old woman,    -   (v) more than 4.1 mg/dL for a 31-40 year old man,    -   (vi) more than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) more than 3.7 mg/dL for a 41-50 year old man,    -   (viii) more than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) more than 3.3 mg/dL for a 51-60 year old man,    -   (x) more than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) more than 3.0 mg/dL for a man over 60 years old, or    -   (xii) more than 2.0 mg/dL for a woman over 60 years old.

The disclosure also pertains to the above method for decreasing foodintake in an individual, inducing satiety in an individual, treatment ofobesity and prevention of obesity.

One aspect of the present disclosure pertains to a method for reducingthe risk of an adverse event in an individual in an individual in needof weight management, comprising: a) determining an approximate serumcreatinine concentration for the individual, and b) not prescribing oradministering (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) more than 4.9 mg/dL for an 18-20 year old man,    -   (ii) more than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) more than 4.5 mg/dL for a 21-30 year old man,    -   (iv) more than 3.2 mg/dL for a 21-30 year old woman,    -   (v) more than 4.1 mg/dL for a 31-40 year old man,    -   (vi) more than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) more than 3.7 mg/dL for a 41-50 year old man,    -   (viii) more than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) more than 3.3 mg/dL for a 51-60 year old man,    -   (x) more than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) more than 3.0 mg/dL for a man over 60 years old, or    -   (xii) more than 2.0 mg/dL for a woman over 60 years old.

One aspect of the present disclosure pertains to a method for selectingan individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management comprising a)determining an approximate serum creatinine concentration for theindividual, and b) not selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has an approximate serumcreatinine concentration of:

-   -   (i) more than 4.9 mg/dL for an 18-20 year old man,    -   (ii) more than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) more than 4.5 mg/dL for a 21-30 year old man,    -   (iv) more than 3.2 mg/dL for a 21-30 year old woman,    -   (v) more than 4.1 mg/dL for a 31-40 year old man,    -   (vi) more than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) more than 3.7 mg/dL for a 41-50 year old man,    -   (viii) more than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) more than 3.3 mg/dL for a 51-60 year old man,    -   (x) more than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) more than 3.0 mg/dL for a man over 60 years old, or    -   (xii) more than 2.0 mg/dL for a woman over 60 years old.

One aspect of the present disclosure pertains to a method for treatmentof a disorder related to 5-HT_(2c) receptor activity in an individual,comprising a) determining the level of renal sufficiency of theindividual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to a method for reducingthe risk of an adverse event in an individual in need of treatment of adisorder related to 5-HT_(2c) receptor activity, comprising a)determining the level of renal sufficiency of the individual, and b)prescribing or administering a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to a method for selectingan individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of a disorder related to5-HT_(2c) receptor activity, comprising a) determining the level ofrenal sufficiency of the individual, and b) selecting the individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to a method for weightmaintenance in an individual, comprising a) determining the level ofrenal sufficiency of the individual, and b) prescribing or administeringa therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to a method for reducingthe risk of an adverse event in an individual in need of weightmaintenance, comprising a) determining the level of renal sufficiency ofthe individual, and b) prescribing or administering a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to a method for selectingan individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight maintenance, comprising a)determining the level of renal sufficiency of the individual, and b)selecting the individual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual, provided that the individual has a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

One aspect of the present disclosure pertains to methods for thetreatment of a disorder related to 5-HT_(2C) receptor activity in anindividual, comprising prescribing or administering to an individual inneed thereof, a therapeutically effective amount of a compound, acrystalline form, a pharmaceutical composition, or a dosage form of thepresent disclosure. In some embodiments, the compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

One aspect of the present disclosure pertains to methods for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

One aspect of the present disclosure pertains to methods for inducingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual in preparation of the individual for bariatricsurgery, comprising administering to an individual in need thereof, atherapeutically effective amount of a compound, a crystalline form, apharmaceutical composition, or a dosage form of the present disclosure.

One aspect of the present disclosure pertains to methods for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual, comprising administering to an individual in needthereof, a therapeutically effective amount of a compound, a crystallineform, a pharmaceutical composition, or a dosage form of the presentdisclosure.

One aspect of the present disclosure pertains to methods for maintainingweight loss, BMI loss, waist circumference loss or body fat percentageloss in an individual following bariatric surgery, comprisingadministering to an individual in need thereof, a therapeuticallyeffective amount of a compound, a crystalline form, a pharmaceuticalcomposition, or a dosage form of the present disclosure.

One aspect of the present disclosure pertains to methods for decreasinghunger in an individual, comprising administering to an individual inneed thereof, a therapeutically effective amount of a compound, acrystalline form, a pharmaceutical composition, or a dosage form of thepresent disclosure.

One aspect of the present disclosure pertains to methods for decreasingfood cravings in an individual, comprising administering to anindividual in need thereof, a therapeutically effective amount of acompound, a crystalline form, a pharmaceutical composition, or a dosageform of the present disclosure.

One aspect of the present disclosure pertains to methods for increasingintermeal interval in an individual, comprising administering to anindividual in need thereof, a therapeutically effective amount of acompound, a crystalline form, a pharmaceutical composition, or a dosageform of the present disclosure.

One aspect of the present disclosure pertains to methods for thetreatment of a disorder selected from: schizophrenia, anxiety,depression, psychoses and alcohol addiction, comprising administering toan individual in need thereof, a therapeutically effective amount of acompound, a crystalline form, a pharmaceutical composition, or a dosageform of the present disclosure.

In some embodiments, the disorder is schizophrenia.

In some embodiments, the disorder is anxiety.

In some embodiments, the disorder is depression.

In some embodiments, the disorder is psychoses.

In some embodiments, the disorder is alcohol addiction.

One aspect of the present disclosure pertains to methods for treating anindividual in need of treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof comprisingprescribing or administering with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual does not have severe renalimpairment or ESRD. An individual in need of treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof includesany individual who would benefit from use of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1)or a pharmaceutically acceptable salt, solvate or hydrate thereof. SinceCompound 1 is a selective 5-HT_(2c) receptor agonist, any individual whowould benefit from use of a selective 5-HT_(2c) receptor agonist isencompassed. For example, the 5-HT_(2C) receptor has been shown to havea role in the regulation of feeding behavior as well as a role inobsessive compulsive disorder, eating disorders, some forms ofdepression and epilepsy. The 5-HT_(2c) receptor has also been shown toplay a role in Alzheimer disease, erectile dysfunction, and sexualdysfunction. Accordingly, 5-HT_(2c) agonists can be useful for thetreatment or prophylaxis of 5-HT_(2c) mediated diseases or disorderssuch as obesity, eating disorders, psychiatric disorders, Alzheimerdisease, sexual dysfunction and disorders related thereto.

In some embodiments, an individual in need of treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is anindividual who wants to lose weight. In some embodiments, an individualin need of treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof is anindividual who wants to maintain weight loss (weight maintenance). Forexample, such an individual in need of treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof can be anindividual who has lost weight and wants to maintain weight loss orprevent, reduce or control weight gain after weight loss.

Once aspect of the disclosure pertains to a compound for use in a methodof preventing or treating obesity or weight gain associated conditionsin a patient, said method comprising determining the level of renalimpairment in said patient and administering said compound at a dosagelevel appropriate for the level of renal impairment to said patient,wherein said patient has previously been determined to have moderate,mild or no renal impairment; wherein said compound 1 is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

For example, Compound 1 or a pharmaceutically acceptable salt, solvateor hydrate thereof should not be prescribed or administered to anindividual with severe renal impairment or ESRD. In addition, forexample, a lower dosage of Compound 1 or a pharmaceutically acceptablesalt, solvate or hydrate thereof can be prescribed or administered to anindividual with mild or moderate renal impairment.

Once aspect of the disclosure pertains to a compound for use in a methodof preventing or treating obesity or weight gain associated conditionsin a patient, said method comprising prescribing said compound to saidpatient, wherein said patient has previously been determined to havemoderate, mild or no renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a compound for use in a methodof preventing or treating obesity or weight gain associated conditionsin a patient, said method comprising determining the level of renalimpairment in said patient and prescribing said compound at a dosagelevel appropriate for the level of renal impairment; wherein saidcompound is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a compound for use in a methodof preventing or treating obesity or weight gain associated conditionsin a patient having [a] moderate, mild or no renal impairment, saidmethod comprising administering said compound to said patient, whereinsaid patient has previously been determined to have moderate, mild or norenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a compound for use in a methodof preventing or treating obesity or weight gain associated conditionsin a patient having [a] moderate, mild or no renal impairment, saidmethod comprising prescribing said compound to said patient, whereinsaid patient has previously been determined to have moderate, mild or norenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a low dosage formulation of acompound for use in a method of preventing or treating obesity or weightgain associated conditions in a patient, said method comprisingadministering said low dosage formulation of the compound to saidpatient, wherein said patient has previously been determined to haverenal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a low dosage formulation of acompound for use in a method of preventing or treating obesity or weightgain associated conditions in a patient, said method comprisingprescribing said low dosage formulation of the compound to said patient,wherein said patient has previously been determined to have renalimpairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a low dosage formulation of acompound for use in a method of preventing a toxic event in a patientbeing treated for obesity or weight gain associated conditions, saidmethod comprising administering said low dosage formulation of thecompound to said patient, wherein said patient has previously beendetermined to have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

Once aspect of the disclosure pertains to a low dosage formulation of acompound for use in a method of preventing a toxic event in a patientbeing treated for obesity or weight gain associated conditions, saidmethod comprising prescribing said low dosage formulation of thecompound to said patient, wherein said patient has previously beendetermined to have renal impairment; wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutical salt, solvate or hydrate thereof.

In one aspect of the disclosure, a test dose or doses of Compound 1 or apharmaceutically acceptable salt, solvate or hydrate thereof can begiven to an individual and the level of a metabolite or metabolites ofCompound 1 or a pharmaceutically acceptable salt, solvate or hydratethereof can be measured for the individual. For example, the level ofmetabolite M1 and/or M5 can be measured. The level of metabolite(s) canbe measured, for example, over different time intervals. Measurement ofmetabolite(s) of Compound 1 or a pharmaceutically acceptable salt,solvate or hydrate thereof have been reported herein, for example, inExample 3 Table 4, Example 4 Table 6, and Example 8 Table 13. If thelevel of metabolite(s) in the individual is below a threshold level thenCompound 1 or a pharmaceutically acceptable salt, solvate or hydratethereof can be prescribed or administered to the individual. However, ifthe level of metabolite(s) in the individual is above a threshold levelthen Compound 1 or a pharmaceutically acceptable salt, solvate orhydrate thereof would be contraindicated for the individual. Thresholdlevels for metabolites M1 and M5 can be determined, for example, bytesting metabolite levels in human clinical trials or estimated, forexample, based on the level of these metabolites in monkeys at the NOAELdose (see for example, Table 9 for M1).

Therefore, one aspect of the disclosure pertains to a method for weightmanagement, decreasing food intake, inducing satiety, preventing ortreating obesity in an individual comprising determining the level of ametabolite of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof in anindividual, and prescribing or administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual provided that the individual has a level of metabolite thatis below a threshold level for the metabolite.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency of severe renal impairment or ESRD indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency of severe renal impairment or ESRD indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency indicating renal impairment indicates that the individual issuitable for prescription of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency indicating renal impairment indicates that theindividual is suitable to receive administration of a reduced dosageregiment of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting weight management in anindividual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 ml/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting weight management inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting weight managementin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of weight management,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable forprescription of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of weight management, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates that the individual is suitable to receiveadministration of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of weight management,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable for prescription ofa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of weight management, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency indicating renal impairmentindicates that the individual is suitable to receive administration of areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of weight management,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of weight management, comprisingmeasuring an approximate serum creatinine concentration for theindividual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting selecting anindividual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of weight management, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of an approximate serum creatinine concentration of

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method of weightmanagement in an individual, said composition comprising(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Further disclosed herein is a low dosage formulation of a compound foruse in a method of weight management in an individual, wherein saidindividual has previously been determined to have renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed is a low dosage formulation of a compound for use in a methodof weight management in an individual, wherein said low dosage reduces atoxic event in said individual to said compound, wherein said individualhas previously been determined to have renal impairment; and whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed is a low dosage formulation of a compound for use ina method of weight management in an individual, wherein said low dosageprevents a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound isR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method of weightmanagement in an individual in need thereof, comprising atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a composition for use in a method ofreducing the risk of an adverse event in an individual in need of weightmanagement, comprising a therapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man;    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a kit for use in a method of weightmanagement in an individual in need thereof, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a kit for reducing the risk of an adverse eventin an individual in need of weight management, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

As throughout the application, in some embodiments, weight managementcomprises weight loss. In some embodiments, weight management comprisesmaintenance of weight loss. In some embodiments, weight managementfurther comprises prescribing or administering a reduced-calorie diet.In some embodiments, weight management further comprises prescribing oradministering a program of regular exercise. In some embodiments, weightmanagement further comprises prescribing or administering both areduced-calorie diet and a program of regular exercise.

In some embodiments, the individual is a patient with an initial bodymass index ≧30 kg/m². In some embodiments, the individual is a patientwith an initial body mass index ≧27 kg/m² in the presence of at leastone weight related comorbid condition. In some embodiments, theindividual is a patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance and sleep apnea. In some embodiments, the individual has aninitial body mass index ≧30 kg/m². In some embodiments, the individualhas an initial body mass index ≧27 kg/m². In some embodiments, theindividual has an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition. In some embodiments, theindividual has an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intoleranceand sleep apnea. In some embodiments, the individual has an initial bodymass index ≧25 kg/m². In some embodiments, the individual has an initialbody mass index ≧25 kg/m² in the presence of at least one weight relatedcomorbid condition. In some embodiments, the individual has an initialbody mass index ≧25 kg/m² in the presence of at least one weight relatedcomorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, the compositions or low dosage formulationscharacterized in the composition or formulation is administered inconjunction with phentermine to the individual. In some embodiments, akit disclosed herein further comprises phentermine.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual. In some embodiments,the individual's ideal body weight is used in the equation and in otherembodiments, the individual's actual body weight is used in theequation. In some embodiments, the individual's serum creatinineconcentration is used to determine the level of renal sufficiency of theindividual.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency of severe renal impairment or ESRD indicates thatthe individual is suitable for prescription of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency of severe renal impairment or ESRD indicates thatthe individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency indicating renal impairment indicates that theindividual is suitable for prescription of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency indicating renal impairment indicates that theindividual is suitable to receive administration of a reduced dosageregiment of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring anapproximate serum creatinine concentration for the individual, wherein ameasurement of an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting decreasing food intake in anindividual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 80 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 80 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 50 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 50 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 30 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting decreasing foodintake in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 30 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of decreasing food intake,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable forprescription of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of decreasing food intake,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable toreceive administration of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of decreasing food intake,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable for prescription ofa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of decreasing food intake,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable to receiveadministration of a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of decreasing food intake,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of decreasing food intake,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting selecting anindividual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of decreasing food intake, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of an approximate serum creatinine concentration of

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofdecreasing food intake in an individual, said composition comprising(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Further disclosed herein is a low dosage formulation of a compound foruse in a method of decreasing food intake in an individual, wherein saidindividual has previously been determined to have renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed is a low dosage formulation of a compound for use in a methodof decreasing food intake in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed is a low dosage formulation of a compound for use ina method of decreasing food intake in an individual, wherein said lowdosage prevents a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound isR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofdecreasing food intake in an individual in need thereof, comprising atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a composition for use in a method ofreducing the risk of an adverse event in an individual in need ofdecreasing food intake, comprising a therapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a kit for use in a method of decreasing foodintake in an individual in need thereof, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of.

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a kit for reducing the risk of an adverse eventin an individual in need of decreasing food intake, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In some embodiments, the individual in need of decreasing food intake isa patient with an initial body mass index ≧30 kg/m². In someembodiments, the individual is a patient with an initial body mass index≧27 kg/m² in the presence of at least one weight related comorbidcondition. In some embodiments, the individual is a patient with aninitial body mass index ≧27 kg/m² in the presence of at least one weightrelated comorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea. In someembodiments, the individual has an initial body mass index ≧30 kg/m². Insome embodiments, the individual has an initial body mass index ≧27kg/m². In some embodiments, the individual has an initial body massindex ≧27 kg/m² in the presence of at least one weight related comorbidcondition. In some embodiments, the individual has an initial body massindex ≧27 kg/m² in the presence of at least one weight related comorbidcondition selected from: hypertension, dyslipidemia, cardiovasculardisease, glucose intolerance and sleep apnea. In some embodiments, theindividual has an initial body mass index ≧25 kg/m². In someembodiments, the individual has an initial body mass index ≧25 kg/m² inthe presence of at least one weight related comorbid condition. In someembodiments, the individual has an initial body mass index ≧25 kg/m² inthe presence of at least one weight related comorbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance and sleep apnea.

In some embodiments, the compositions or low dosage formulationscharacterized in the composition or formulation is administered inconjunction with phentermine to the individual. In some embodiments, akit disclosed herein further comprises phentermine.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual. In some embodiments,the individual's ideal body weight is used in the equation and in otherembodiments, the individual's actual body weight is used in theequation. In some embodiments, the individual's serum creatinineconcentration is used to determine the level of renal sufficiency of theindividual.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency of severe renal impairment or ESRD indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency of severe renal impairment or ESRD indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency indicating renal impairment indicates that the individual issuitable for prescription of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring the level of renalsufficiency of the individual, wherein a measurement of a level of renalsufficiency indicating renal impairment indicates that the individual issuitable to receive administration of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting inducing satiety in anindividual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or.    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting inducing satiety inan individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable to receive administration of a therapeuticallyeffective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of inducing satiety,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable forprescription of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of inducing satiety, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates that the individual is suitable to receiveadministration of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of inducing satiety,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable for prescription ofa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of inducing satiety, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency indicating renal impairmentindicates that the individual is suitable to receive administration of areduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of inducing satiety,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of inducing satiety, comprisingmeasuring an approximate serum creatinine concentration for theindividual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting selecting anindividual for treatment, with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of inducing satiety, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of an approximate serum creatinine concentration of

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofinducing satiety in an individual, said composition comprising(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Further disclosed herein is a low dosage formulation of a compound foruse in a method of inducing satiety in an individual, wherein saidindividual has previously been determined to have renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed is a low dosage formulation of a compound for use in a methodof inducing satiety in an individual, wherein said low dosage reduces atoxic event in said individual to said compound, wherein said individualhas previously been determined to have renal impairment; and whereinsaid compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed is a low dosage formulation of a compound for use ina method of inducing satiety in an individual, wherein said low dosageprevents a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofinducing satiety in an individual in need thereof, comprising atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a composition for use in a method ofreducing the risk of an adverse event in an individual in need ofinducing satiety, comprising a therapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a kit for use in a method of inducingsatiety in an individual in need thereof, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 0.2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a kit for reducing the risk of an adverse eventin an individual in need of inducing satiety, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In some embodiments, the individual in need of inducing satiety is apatient with an initial body mass index ≧30 kg/m². In some embodiments,the individual is a patient with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related comorbid condition. In someembodiments, the individual is a patient with an initial body mass index≧27 kg/m² in the presence of at least one weight related comorbidcondition selected from: hypertension, dyslipidemia, cardiovasculardisease, glucose intolerance and sleep apnea. In some embodiments, theindividual has an initial body mass index ≧30 kg/m². In someembodiments, the individual has an initial body mass index ≧27 kg/m². Insome embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid condition.In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea. In some embodiments, the individualhas an initial body mass index ≧25 kg/m². In some embodiments, theindividual has an initial body mass index ≧25 kg/m² in the presence ofat least one weight related comorbid condition. In some embodiments, theindividual has an initial body mass index ≧25 kg/m² in the presence ofat least one weight related comorbid condition selected from:hypertension, dyslipidemia, cardiovascular disease, glucose intoleranceand sleep apnea.

In some embodiments, the compositions or low dosage formulationscharacterized in the composition or formulation is administered inconjunction with phentermine to the individual. In some embodiments, akit disclosed herein further comprises phentermine.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual. In some embodiments,the individual's ideal body weight is used in the equation and in otherembodiments, the individual's actual body weight is used in theequation. In some embodiments, the individual's serum creatinineconcentration is used to determine the level of renal sufficiency of theindividual.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency of severe renal impairment or ESRD indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency of severe renal impairment or ESRD indicates thatthe individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency indicating renal impairment indicates that theindividual is suitable for prescription of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency indicating renal impairment indicates that theindividual is suitable to receive administration of a reduced dosageregiment of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring an approximateserum creatinine concentration for the individual, wherein a measurementof an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting treatment of obesity in anindividual in need thereof, comprising measuring an approximate serumcreatinine concentration, for the individual, wherein a measurement ofan approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 80 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 50 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting treatment of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting treatment ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 30 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of treatment of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable forprescription of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of treatment of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable toreceive administration of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of treatment of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable for prescription ofa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of treatment of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable to receiveadministration of a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of treatment of obesity,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of treatment of obesity,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting selecting anindividual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of treatment of obesity, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of an approximate serum creatinine concentration of

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method oftreatment of obesity in an individual, said composition comprising(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Further disclosed herein is a low dosage formulation of a compound foruse in a method of treatment of obesity in an individual, wherein saidindividual has previously been determined to have renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed is a low dosage formulation of a compound for use in a methodof treatment of obesity in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed is a low dosage formulation of a compound for use ina method of treatment of obesity in an individual, wherein said lowdosage prevents a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method oftreatment of obesity in an individual in need thereof, comprising atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a composition for use in a method ofreducing the risk of an adverse event in an individual in need oftreatment of obesity, comprising a therapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a kit for use in a method of treatment ofobesity in an individual in need thereof, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a kit for reducing the risk of an adverse eventin an individual in need of treatment of obesity, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In some embodiments, treatment of obesity comprises weight loss. In someembodiments, treatment of obesity comprises maintenance of weight loss.In some embodiments, treatment of obesity further comprises prescribingor administering a reduced-calorie diet. In some embodiments, treatmentof obesity further comprises prescribing or administering a program ofregular exercise. In some embodiments, treatment of obesity furthercomprises prescribing or administering both a reduced-calorie diet and aprogram of regular exercise.

In some embodiments, the individual in need of treatment of obesity is apatient with an initial body mass index ≧30 kg/m². In some embodiments,the individual is a patient with an initial body mass index ≧27 kg/m² inthe presence of at least one weight related comorbid condition. In someembodiments, the individual is a patient with an initial body mass index≧27 kg/m² in the presence of at least one weight related comorbidcondition selected from: hypertension, dyslipidemia, cardiovasculardisease, glucose intolerance and sleep apnea. In some embodiments, theindividual has an initial body mass index ≧30 kg/m². In some someembodiments, the individual has an initial body mass index 27 kg/m². Insome embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid condition.In some embodiments, the individual has an initial body mass index ≧27kg/m² in the presence of at least one weight related comorbid conditionselected from: hypertension, dyslipidemia, cardiovascular disease,glucose intolerance and sleep apnea.

In some embodiments, the compositions or low dosage formulationscharacterized in the composition or formulation is administered inconjunction with phentermine to the individual. In some embodiments, akit disclosed herein further comprises phentermine.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual. In some embodiments,the individual's ideal body weight is used in the equation and in otherembodiments, the individual's actual body weight is used in theequation. In some embodiments, the individual's serum creatinineconcentration is used to determine the level of renal sufficiency of theindividual.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency selected from the group consisting of: no renalimpairment, mild renal impairment, and moderate renal impairmentindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency of severe renal impairment or ESRD indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency of severe renal impairment or ESRD indicates thatthe individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring the level ofrenal sufficiency of the individual, wherein a measurement of a level ofrenal sufficiency indicating renal impairment indicates that theindividual is suitable for prescription of a reduced dosage regiment of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring the levelof renal sufficiency of the individual, wherein a measurement of a levelof renal sufficiency indicating renal impairment indicates that theindividual is suitable to receive administration of a reduced dosageregiment of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ora pharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring an approximateserum creatinine concentration for the individual, wherein a measurementof an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting prevention of obesity in anindividual in need thereof, comprising measuring an approximate serumcreatinine concentration for the individual, wherein a measurement of anapproximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 80 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 80 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 50 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 50 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting prevention of obesityin an individual in need thereof, comprising measuring a creatinineclearance rate using the Cockcroft-Gault equation for the individualwherein a measurement of a creatinine clearance rate of greater thanabout 30 mL/minute using the Cockcroft-Gault equation indicates that theindividual is suitable for prescription of a therapeutically effectiveamount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed herein is a method for assisting prevention ofobesity in an individual in need thereof, comprising measuring acreatinine clearance rate using the Cockcroft-Gault equation for theindividual wherein a measurement of a creatinine clearance rate ofgreater than about 30 mL/minute using the Cockcroft-Gault equationindicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of prevention of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable forprescription of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of prevention of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency selected from thegroup consisting of: no renal impairment, mild renal impairment, andmoderate renal impairment indicates that the individual is suitable toreceive administration of a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of prevention of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable for prescription ofa reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of prevention of obesity,comprising measuring the level of renal sufficiency of the individual,wherein a measurement of a level of renal sufficiency indicating renalimpairment indicates that the individual is suitable to receiveadministration of a reduced dosage regimen of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting reducing the risk ofan adverse event in an individual in need of prevention of obesity,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60*years old

indicates that the individual is suitable for prescription of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting reducing the risk of anadverse event in an individual in need of prevention of obesity,comprising measuring an approximate serum creatinine concentration forthe individual, wherein a measurement of an approximate serum creatinineconcentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is suitable to receive administration of atherapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a method for assisting selecting anindividual for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of a level of renal sufficiency selected from the groupconsisting of: no renal impairment, mild renal impairment, and moderaterenal impairment indicates the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed herein is a method for assisting selecting an individual fortreatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof from aplurality of individuals in need of prevention of obesity, comprisingmeasuring the level of renal sufficiency of the individual, wherein ameasurement of an approximate serum creatinine concentration of

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old

indicates that the individual is selected for treatment with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofprevention of obesity in an individual, said composition comprising(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinsaid individual has previously been determined to have a level of renalsufficiency selected from the group consisting of: no renal impairment,mild renal impairment, and moderate renal impairment.

Further disclosed herein is a low dosage formulation of a compound foruse in a method of prevention of obesity in an individual, wherein saidindividual has previously been determined to have renal impairment;wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Alsodisclosed is a low dosage formulation of a compound for use in a methodof prevention of obesity in an individual, wherein said low dosagereduces a toxic event in said individual to said compound, wherein saidindividual has previously been determined to have renal impairment; andwherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof. Inaddition, disclosed is a low dosage formulation of a compound for use ina method of prevention of obesity in an individual, wherein said lowdosage prevents a toxic event in said individual to said compound,wherein said individual has previously been determined to have renalimpairment; and wherein said compound is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof.

Further disclosed herein is a composition for use in a method ofprevention of obesity in an individual in need thereof, comprising atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In addition, disclosed herein is a composition for use in a method ofreducing the risk of an adverse event in an individual in need ofprevention of obesity, comprising a therapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, whereinthe individual has an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Further disclosed herein is a kit for use in a method of prevention ofobesity in an individual in need thereof, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

Also disclosed herein is a kit for reducing the risk of an adverse eventin an individual in need of prevention of obesity, comprising: a) atherapeutically effective amount ofR)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof, and b)instructions indicating that the compound is to be administered to anindividual having an approximate serum creatinine concentration of:

-   -   (i) less than 4.9 mg/dL for an 18-20 year old man,    -   (ii) less than 3.5 mg/dL for an 18-20 year old woman,    -   (iii) less than 4.5 mg/dL for a 21-30 year old man,    -   (iv) less than 3.2 mg/dL for a 21-30 year old woman,    -   (v) less than 4.1 mg/dL for a 31-40 year old man,    -   (vi) less than 2.9 mg/dL for a 31-40 year old woman,    -   (vii) less than 3.7 mg/dL for a 41-50 year old man,    -   (viii) less than 2.7 mg/dL for a 41-50 year old woman,    -   (ix) less than 3.3 mg/dL for a 51-60 year old man,    -   (x) less than 2.4 mg/dL for a 51-60 year old woman,    -   (xi) less than 3.0 mg/dL for a man over 60 years old, or    -   (xii) less than 2.0 mg/dL for a woman over 60 years old.

In some embodiments, the prevention of obesity comprises weight loss. Insome embodiments, the prevention of obesity comprises maintenance ofweight loss. In some embodiments, the prevention of obesity furthercomprises prescribing or administering a reduced-calorie diet. In someembodiments, the prevention of obesity further comprises prescribing oradministering a program of regular exercise. In some embodiments, theprevention of obesity further comprises prescribing or administeringboth a reduced-calorie diet and a program of regular exercise.

In some embodiments, the individual in need of prevention of obesity isa patient with an initial body mass index ≧27 kg/m² in the presence ofat least one weight related comorbid condition. In some embodiments, theindividual is a patient with an initial body mass index ≧27 kg/m² in thepresence of at least one weight related comorbid condition selectedfrom: hypertension, dyslipidemia, cardiovascular disease, glucoseintolerance and sleep apnea. In some embodiments, the individual has aninitial body mass index ≧27 kg/m². In some embodiments, the individualhas an initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition. In some embodiments, the individualhas an initial body mass index ≧27 kg/m² in the presence of at least oneweight related comorbid condition selected from: hypertension,dyslipidemia, cardiovascular disease, glucose intolerance and sleepapnea. In some embodiments, the individual has an initial body massindex ≧25 kg/m². In some embodiments, the individual has an initial bodymass index ≧25 kg/m² in the presence of at least one weight relatedcomorbid condition. In some embodiments, the individual has an initialbody mass index ≧25 kg/m² in the presence of at least one weight relatedcomorbid condition selected from: hypertension, dyslipidemia,cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, the compositions or low dosage formulationscharacterized in the composition or formulation is administered inconjunction with phentermine to the individual. In some embodiments, akit disclosed herein further comprises phentermine.

In some embodiments, the Cockcroft-Gault equation is used to determinethe level of renal sufficiency of the individual. In some embodiments,the individual's ideal body weight is used in the equation and in otherembodiments, the individual's actual body weight is used in theequation. In some embodiments, the individual's serum creatinineconcentration is used to determine the level of renal sufficiency of theindividual.

Further disclosed herein is a method of weight management, decreasingfood intake, inducing satiety or treating or preventing obesity in anindividual said method comprising administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual and monitoring the individual for accumulation of ametabolite of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof. Forexample, disclosed herein is a method of weight management decreasingfood intake, inducing satiety or treating or preventing obesity in anindividual said method comprising administering(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof to theindividual and monitoring the individual for accumulation of ametabolite of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-H-3-benzazepineor a pharmaceutically acceptable salt, solvate or hydrate thereof anddiscontinuing administration if said metabolite exceeds a predeterminedsafe level. A safe level can be determined, for example, by a healthcare practitioner or a regulatory agency. A metabolite of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or apharmaceutically acceptable salt, solvate or hydrate thereof can be, forexample, metabolite M1 (lorcaserin sulfamate) and/or M5 (N-carbamoylglucuronide of lorcaserin).

Other uses of the disclosed methods will become apparent to those in theart based upon, inter alia, a review of this patent document.

EXAMPLES

The examples are provided to further define the disclosure without,however, limiting the disclosure to the specifics of these examples.

Example 1

Clinical Trial APD356-016. Pharmacokinetics of Lorcaserin in RenalImpairment

The interaction of renal insufficiency with the pharmacokinetics,tolerability and safety of lorcaserin were evaluated in a formal PKstudy in subjects with renal impairment and in the populations studiedin phase 2 and phase 3 clinical studies.

The pharmacokinetic properties of lorcaserin in subjects with varyingdegrees of renal impairment were evaluated in clinical trial APD356-016.At the time of study conduct and analysis, subjects were assigned torenal impairment groups based on creatinine clearance calculated usingIDEAL body weight (Table 1). This calculation was used to avoidoverestimation of creatinine clearance due to the excess body weight(overweight and obese subjects were enrolled in the trial). Summaries ofpharmacokinetic properties by group assignment using creatinineclearance calculated using ACTUAL body weights are also provided in thesections that follow.

TABLE 1 Group Assignments in APD356-016 Renal Impairment Study GroupEstimated Creatinine Clearance using Description Ideal Body Weight(mL/min) Normal renal function >80 mL/min Mild renal impairment 51-80mL/min Moderate renal impairment 31-50 mL/min Severe renal impairment5-30 mL/min not receiving dialysis End stage renal disease ESRDrequiring hemodialysis Source: APD356-016 CSR, Table 1

Example 2

Lorcasein

Consistent with the metabolism of lorcaserin through multiple pathways,and the low renal excretion of lorcascrin demonstrated in clinical studyAPD356-006, lorcascrin exposure was not clearly affected by renalimpairment. The 90% confidence interval for geometric mean ratios (GMR)of lorcaserin AUC_(0-inf) in renal impairment relative to normal wasslightly above the equivalence range in the mild and moderate impairmentgroups, but not in the severe impairment groups (Table 2, FIG. 1A, 1B).

TABLE 2 Geometric Mean Ratios of Lorcaserin Plasma PharmacokineticParameters Geometric Mean Ratios of LSM (90% Confidence Intervals) of(R)-8- chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Relative toPharmacokinetic Normal Renal Function Group (n = 8 per Group) ParametersMild Moderate Severe Using Ideal Body Weight (original CSR analysis) N =8 N = 8 N = 8 C_(max) 0.991 (0.764, 1.29) 0.697 (0.537, 0.904) 0.686(0.529, 0.891) AUC_(last) 1.31 (1.01, 1.69) 1.02 (0.791, 1.32) 0.933(0.723, 1.20) AUC_(0-inf) 1.30 (1.01, 1.67) 1.03 (0.806, 1.32) 0.931(0.727, 1.19) Note: Group assignments based on ideal body weight Source:APD356-016 CSR, Table 14.2.1.3 Using Actual Body Weight N = 10 N = 8 N =1 C_(max) 0.819 (0.652, 1.03) 0.738 (0.579, 0.941) 0.468 (0.267, 0.821)AUC_(last) 0.912 (0.723, 1.15) 0.868 (0.678, 1.11) 0.861 (0.487, 1.52)AUC_(0-inf) 0.921 (0.735, 1.15) 0.869 (0.683, 1.11) 0.861 (0.494, 1.50)Group assignments based on ideal body weight were reported in theAPD356-016 Clinical Study Report Source LSM—Least-squares meansCSR—Clinical Study Report AUC_(last)—area under the plasma concentration-time curve from time zero to the last time point AUC_(0-inf)—area underthe plasma concentration -time curve from time zero to infinity

A weak negative correlation was observed between renal clearance oflorcaserin and calculated creatinine clearance using ideal body weight(FIG. 2), but no correlation was observed with creatinine clearancecalculated using actual body weight (FIG. 2). The weak correlation isunlikely to be meaningful, given that renal clearance represents a smallfraction of total lorcaserin clearance (fractional excretion 2.2% insubjects with normal renal function). Total lorcaserin clearance was notsignificantly correlated with creatinine clearance (FIG. 3). Lorcaserinwas not removed by hemodialysis.

Reassignment of subjects to renal impairment groups based on creatinineclearance calculated using actual body weight instead of ideal bodyweight had little impact on the overall interpretation of the resultsfor lorcaserin (Table 3).

TABLE 3 Mean Lorcaserin Pharmacokinetic Parameters after a 10 mg Dose ofLorcaserin: Based in Renal Function Assignments using IDEAL or ACTUALBody Weight GROUP ASSIGNMENTS USING PK IDEAL BODY WEIGHT Parameters^(a)Normal Mild Moderate Severe mean (SD) N = 8 N = 8 N = 8 N = 8 AUC_(0-t)0.482 (0.101) 0.623 (0.088) 0.515 (0.190) 0.469 (0.172) (μg · hr/mL)AUC_(0-inf) 0.501 (0.104) 0.644 (0.089) 0.538 (0.190) 0.486 (0.179) (μg· hr/mL) % AUC_(0-inf) 3.81 (1.57) 3.36 (0.87) 4.92 (2.68) 3.59 (1.01)Extrapolated C_(max) (ng/mL) 37.0 (8.7) 36.3 (8.0) 26.2 (8.3) 26.4(11.7) t_(max) (hr)^(a) 2.00 (1.00-3.00) 4.50 (1.00-8.00) 2.50(2.00-3.00) 3.00 (1.00-4.00) Cl/F (L/hr) 17.5 (3.4) 13.3 (1.8) 17.7(6.6) 19.7 (8.0) Cl_(R)/F (L/hr) 0.392 (0.202) 0.533 (0.322) 0.667(0.228) 0.657 (0.373) Cl_(NR)/F (L/hr) 17.1 (3.3) 12.8 (1.6) 17.0 (6.5)19.0 (7.8) Vz/F (L) 276 (53) 248 (40) 399 (132) 401 (103) MRT_(inf) (hr)14.8 (2.2) 18.0 (3.0) 21.1 (2.8) 21.7 (5.7) Ae₀₋₁₂₀ (μg) 185 (78) 326(156) 327 (100) 280 (140) fe₀₋₁₂₀ 0.0220 (0.0092) 0.0386 (0.0185) 0.0387(0.0118) 0.0332 (0.0166) T_(1/2z) (hr) 11.0 (1.4) 13.0 (1.9) 15.9 (2.1)15.0 (3.6) GROUP ASSIGNMENTS USING PK ACTUAL BODY WEIGHT Parameters^(a)Normal Mild Moderate Severe mean (SD) N = 13 N = 10 N = 8 N = 1AUC_(0-t) 0.549 (0.129) 0.513 (0.164) 0.497 (0.186) 0.461 (NA) (μg ·hr/mL) AUC_(0-inf) 0.569 (0.132) 0.535 (0.165) 0.516 (0.191) 0.478 (NA)(μg · hr/mL) % AUC_(0-inf) 3.57 (1.31) 4.54 (2.49) 3.74 (1.16) 3.70 (NA)Extrapolated C_(max) (ng/mL) 36.0 (8.0) 30.2 (10.4) 27.6 (11.6) 16.4(NA) t_(max) (hr)^(a) 2.0 (1.00-8.00) 2.5 (1.00-3.00) 2.5 (1.00-4.00)4.0 (4.00-4.00) Cl/F (L/hr) 15.6 (3.7) 17.3 (5.9) 18.9 (8.4) 17.6 (NA)Cl_(R)/F (L/hr) 0.468 (0.291) 0.617 (0.275) 0.663 (0.340) 0.436 (NA)Cl_(NR)/F (L/hr) 15.1 (3.7) 16.7 (5.7) 18.2 (8.2) 17.2 (NA) Vz/F (L) 266(51) 361 (130) 381 (116) 479 (NA) MRT_(inf) (hr) 16.5 (3.3) 19.3 (3.5)20.8 (4.4) 30.8 (NA) Ae₀₋₁₂₀ (μg) 257 (152) 297 (100) 304 (142) 204 (NA)fe₀₋₁₂₀ 0.0304 (0.0180) 0.0352 (0.0118) 0.0360 (0.0168) 0.0242 (NA)T_(1/2z) (hr) 12.1 (2.0) 14.6 (2.7) 14.9 (3.3) 18.8 (NA) ^(a)Median(minimum-maximum) Source: APD356-016 CSR: Tables 14.2.1.2.1, 14.2.1.2.2,14.2.1.2.3, 14.2.1.2.4, 14.2.1.2.5, 14.2.1.2.6 AUC_(0-t)—area under theplasma concentration -time curve from time zero to time t t_(max)—timeto reach maximum plasma concentration Cl/F—apparent clearanceCl_(R)/f—apparent renal clearance Cl_(NR)/F—apparent non-renal clearanceVz/F—apparent volume of distribution MRT_(inf)—mean residence time toinfinity Ae₀₋₁₂₀—amount excreted in the urine over 120 hours post dosingFe₀₋₁₂₀—fraction excreted in the urine over 120 hours post dosingT_(1/2z)—elimination half-life

Example 3

M1

In contrast to the parent compound lorcaserin, the pharmacologicallyinactive major circulating metabolite M1 (lorcascrin sulfamate) wassignificantly affected by renal impairment. Although M1 is a minormetabolite in urine, plasma exposure was increased in subjects withrenal impairment (Table 4, FIGS. 1C, 1D). AUC_(0-inf) of M1, but notC_(max), was negatively correlated with creatinine clearance (Table 5).M1 was not removed by hemodialysis.

Similar results were obtained whether creatinine clearance wascalculated using ideal body weight (as was done in the APD356-016Clinical Study Report), or actual body weight (which can overestimatecreatinine clearance, since creatinine is not produced by adiposetissue).

The highest mean M1 exposure (AUC_(0-inf)=23.6) was observed in thesevere renal impairment group (Table 4). This relatively high value waslargely driven by a single subject, 3285-009, who had an AUC_(0-inf)value of 101 μg·hr/mL and a C_(max) of 542 ng/mL. This subject'scalculated creatinine clearance was 28.3 mL/min using ideal body weight,or 37.9 mL/min using actual body weight. As a result, when the studydata were reanalyzed using group assignments according to actual bodyweight, subject 3285-009 was assigned to the moderate renal impairmentgroup, driving the mean exposure higher in that group.

TABLE 4 Mean M1 Plasma and Urine Pharmacokinetic Parameters after a 10mg Oral Dose of Lorcaserin GROUP ASSIGNMENTS USING PK IDEAL BODY WEIGHTParameters^(a) Normal Mild Moderate Severe mean (SD) N = 8 N = 8 N = 8 N= 8 AUC_(0-t) 0.482 (0.101) 0.623 (0.088) 0.515 (0.190) 0.469 (0.172)(μg · hr/mL) AUC_(0-inf) 0.501 (0.104) 0.644 (0.089) 0.538 (0.190) 0.486(0.179) (μg · hr/mL) % AUC_(0-inf) 3.81 (1.57) 3.36 (0.87) 4.92 (2.68)3.59 (1.01) Extrapolated C_(max) (ng/mL) 37.0 (8.7) 36.3 (8.0) 26.2(8.3) 26.4 (11.7) t_(max) (hr)^(a) 2.00 (1.00-3.00) 4.50 (1.00-8.00)2.50 (2.00-3.00) 3.00 (1.00-4.00) Cl/F (L/hr) 17.5 (3.4) 13.3 (1.8) 17.7(6.6) 19.7 (8.0) Cl_(R)/F (L/hr) 0.392 (0.202) 0.533 (0.322) 0.667(0.228) 0.657 (0.373) Cl_(NR)/F (L/hr) 17.1 (3.3) 12.8 (1.6) 17.0 (6.5)19.0 (7.8) Vz/F (L) 276 (53) 248 (40) 399 (132) 401 (103) MRT_(inf) (hr)14.8 (2.2) 18.0 (3.0) 21.1 (2.8) 21.7 (5.7) Ae₀₋₁₂₀ (μg) 185 (78) 326(156) 327 (100) 280 (140) fe₀₋₁₂₀ 0.0220 (0.0092) 0.0386 (0.0185) 0.0387(0.0118) 0.0332 (0.0166) T_(1/2z) (hr) 11.0 (1.4) 13.0 (1.9) 15.9 (2.1)15.0 (3.6) GROUP ASSIGNMENTS USING PK ACTUAL BODY WEIGHT Parameters^(a)Normal Mild Moderate Severe mean (SD) N = 13 N = 10 N = 8 N = 1AUC_(0-t) 0.549 (0.129) 0.513 (0.164) 0.497 (0.186) 0.461 (NA) (μg ·hr/mL) AUC_(0-inf) 0.569 (0.132) 0.535 (0.165) 0.516 (0.191) 0.478 (NA)(μg · hr/mL) % AUC_(0-inf) 3.57 (1.31) 4.54 (2.49) 3.74 (1.16) 3.70 (NA)Extrapolated C_(max) (ng/mL) 36.0 (8.0) 30.2 (10.4) 27.6 (11.6) 16.4(NA) t_(max) (hr)^(a) 2.0 (1.00-8.00) 2.5 (1.00-3.00) 2.5 (1.00-4.00)4.0 (4.00-4.00) Cl/F (L/hr) 15.6 (3.7) 17.3 (5.9) 18.9 (8.4) 17.6 (NA)Cl_(R)/F (L/hr) 0.468 (0.291) 0.617 (0.275) 0.663 (0.340) 0.436 (NA)Cl_(NR)/F (L/hr) 15.1 (3.7) 16.7 (5.7) 18.2 (8.2) 17.2 (NA) Vz/F (L) 266(51) 361 (130) 381 (116) 479 (NA) MRT_(inf) (hr) 16.5 (3.3) 19.3 (3.5)20.8 (4.4) 30.8 (NA) Ae₀₋₁₂₀ (μg) 257 (152) 297 (100) 304 (142) 204 (NA)fe₀₋₁₂₀ 0.0304 (0.0180) 0.0352 (0.0118) 0.0360 (0.0168) 0.0242 (NA)T_(1/2z) (hr) 12.1 (2.0) 14.6 (2.7) 14.9 (3.3) 18.8 (NA) b Median(minimum-maximum) Source: APD356-016 CSR: Tables 14.2.1.2.1, 14.2.1.2.2,14.2.1.2.3, 14.2.1.2.4, 14.2.1.2.5, 14.2.1.2.6

M1 exposure (AUC_(0-inf)) was significantly inversely correlated withcreatinine clearance; C_(max) was not correlated with creatinineclearance (Table 5, FIG. 4).

TABLE 5 Correlation Analysis: M1 Exposure as a Function of CreatinineClearance CrCl Calculated with CrCl Calculated with Ideal BW Actual BWParameter AUCinf C_(max) AUCinf C_(max) N 32 32 32 32 Spearman r −0.8076−0.2051 −0.7716 −0.2282 95% CI −0.9042 to −0.6322 −0.5248 to 0.1652−0.8852 to −0.5714 −0.5421 to 0.1416 P value <0.0001 0.2601 <0.00010.2090 (two-tailed) Source: APD356-016 CSR, Tables 14.2.2.2.1.14.2.2.2.2, 14.2.2.2.3, and 14.2.2.2.4; Listing 16.2.4; non-parametric(Spearman) correlation analysis generated using GraphPad Prism version5.01 for Windows, GraphPad Software, San Diego California USA Spearmanr—Spearman's rank correlation coefficient Cl—confidence interval

To better assess the potential implications of M1 levels in subjectswith renal impairment, steady state M1 exposure following lorcaserin 10mg BID administration was modeled using simulations and noncompartmentalanalysis based upon data from pharmacokinetic studies with once daily(QD) dosing. This modeling is discussed below in Example 5.

Example 4

M5

Plasma exposure of M5 (N-carbamoyl glucuronide of lorcaserin), the majorurinary metabolite, was increased with increasing renal impairment. Thefractional excretion of M5 ranged from 35% in severe renal impairment to48% in normal renal function. Plasma exposure of M5 increased withdecreasing creatinine clearance (FIG. 5, Table 6). M5 AUC_(0-inf), butnot C_(max), was significantly correlated with creatinine clearance(Table 7). M5 was partially removed by hemodialysis, with an extractionratio of 18.4%.

TABLE 6 Mean M5 Plasma and Urine Pharmacokinetic Parameters after a 10mg Oral Dose of Lorcaserin Pharmacokinetic Mean PharmacokineticParameters for M5 Parameters ESRD ESRD Mean (SD) Normal Mild ModerateSevere (Period 1) (Period 2) Group Assignments using IDEAL Body Weight N= 8 N = 8 N = 8 N = 8 N = 8 N = 8 AUC_(0-t) 0.345 (0.111) 0.482 (0.136)0.944 (0.343) 2.29 (1.70) 9.53 (4.94) 8.24 (4.02) (μg ·hr/mL)AUC_(0-inf) 0.475 (0.155) 0.583 (0.146) 1.10 (0.31) 2.47 (1.72) 11.2(5.6) 11.9 (6.0) (μg ·hr/mL) % AUC 26.3 (51.6) 17.7 (5.1) 15.6 (10.7)8.46 (5.01) 14.7 (7.3) 26.9 (15.4) Extrapolated C_(max) (ng/mL) 70.5(22.3) 62.4 (10.7) 96.4 (23.7) 153 (57) 300 (139) 231 (93) MRT_(inf)(hr) 14.6 (10.9) 13.5 (3.0) 18.5 (4.6) 20.0 (7.5) 38.6 (9.5) 59.1 (27.5)t_(max) (hr)^(a) 1.00 (1.00-2.00) 2.00 (1.00-3.00) 2.00 (1.00-3.00) 2.50(2.00-4.00) 3.00 (2.00-6.00) 3.10 (2.10-6.00) t_(1/2z) (hr) 12.2 (9.3)10.7 (2.6) 15.4 (4.8) 14.9 (5.5) 25.7 (7.2) 40.5 (20.2) Ae (μg) 8540(1722) 7160 (1375) 8000 (1975) 6300 (1249) NA NA Fe₀₋₁₂₀ 0.476 (0.096)0.399 (0.077) 0.446 (0.110) 0.351 (0.070) NA NA Group Assignments usingACTUAL Body Weight N = 13 N = 10 N = 8 N = 1 N = 8 N = 8 AUC_(last)0.381 (0.104) 0.914 (0.421) 1.51 (0.676) 6.31 9.53 (4.94) 8.24 (4.02)(μg ·hr/mL) AUC_(0-inf) 0.498 (0.126) 1.04 (0.407) 1.70 (0.71) 6.48 11.2(5.6) 11.9 (6.0) (μg ·hr/mL) % AUC 23.1 (11.5) 14.5 (9.8) 12.1 (6.7)2.59 14.7 (7.3) 26.9 (15.4) Extrapolated C_(max) (ng/mL) 66.2 (19.3)91.9 (27.4) 134 (57.5) 214 300 (139) 231 (93) MRT_(inf) (hr) 14.2 (8.5)16.6 (5.1) 18.5 (5.3) 33.4 38.6 (9.5) 59.1 (27.5) t_(max) (hr)^(a) 2(1-3) 2 (1-3) 2 (2-4) 4 3.00 (2.00-6.00) 3.10 (2.10-6.00) t_(1/2z) (hr)11.7 (7.2) 13.5 (5.2) 14.4 (4.5) 23.1 25.7 (7.2) 40.5 (20.2) Ae (μg)8210 (1391) 7470 (2100) 6480 (1554) 6720 NA NA Fe₀₋₁₂₀ 0.458 (0.078)0.417 (0.117) 0.361 (0.087) 0.375 NA NA NA: Not applicable c Median(minimum-maximum) Source: APD356-016 CSR: Table 14.2.3.2.1, 14.2.3.2.2,14.2.3.2.3, 14.2.3.2.4, 14.2.3.2.5, 14..2.3.2.6

TABLE 7 Correlation Analysis: M5 Clearance as a Function of CreatinineClearance CrCl Calculated with CrCl Calculated with Ideal BW Actual BWParameter AUC_(inf) C_(max) AUC_(inf) C_(max) N 32 32 32 32 Spearman r−0.8076 −0.2051 −0.7716 −0.2282 95% CI −0.9042 to −0.6322 −0.5248 to0.1652 −0.8852 to −0.5714 −0.5421 to 0.1416 P value <0.0001 0.2601<0.0001 0.2090 (two-tailed) Abbreviations: CrCl = Creatinine clearance,BW = body weight APD356-016 CSR, Tables 14.2.3.2.1. 14.2.3.2.2,14.2.3.2.3, and 14.2.3.2.4; Listing 16.2.4; non- parametric (Spearman)correlation analysis generated using GraphPad Prism version 5.01 forWindows, GraphPad Software, San Diego California USA

Example 5

Discussion of M1 and M5 Exposure in Renal Impairment

M1 and M5 exposures increased in patients with moderate to severe renalimpairment; lorcaserin did not. To better assess the potentialimplications of M1 and M5 levels, steady state exposures followinglorcaserin 10 mg BID dosing were modeled using simulations andnoncompartmental analysis based upon data from pharmacokinetic studieswith once daily (QD) dosing. (PDR-09-151; Table 8). The predicted M1C_(max) values in subjects with normal and mild renal impairment are 130ng/ml and 207 ng/ml, respectively, which are consistent with the mean M1C_(max) levels of 196 ng/mL observed in patients at Week 12 followinglorcaserin 10 mg BID in APD356-009 study (APD356-009 CSR, Table14.3.164). Based on the modeled values, subjects with moderate renalimpairment are expected to achieve M1 C_(max) levels of 414 ng/mL, whilethose with severe impairment will reach 1090 ng/mL. Total dailyexposures (AUC₂₄) are predicted to be 9670 and 25,500 hr·ng/mL inmoderate and severe renal impairment, respectively.

M1 exposures achieved in preclinical toxicology studies were well abovethe exposures observed in the APD356-016 clinical study (meanAUC_(0-inf)=23.6 μg·hr/mL in the severe renal impairment group; Table9), or the modeled steady state exposures (Table 8). In monkeys dosedwith 2 mg/kg/day lorcaserin (the no observable adverse event level(NOAEL)) for 52 weeks, the M1 AUC_(0-inf) values of 41 and 62 μg·hr/mL(female and male) are 1.6-2.4 times the predicted daily exposure in aperson with severe renal impairment. At the 10 mg/kg/day dose, theAUC_(0-inf) exposure margin is about 12 fold. C_(max) values of 4.58 and5.01 μg/mL (females and males) are approximately 5 times the predictedC_(max) in a person with severe renal impairment who takes lorcaserin 10mg BID to steady state. At a dose of 10 mg/kg day in the monkey, theC_(max) margin is approximately 20-25 times the predicted exposure in aperson with severe renal impairment.

Predicted M5 exposure in a person with severe renal impairment is alsowell below the exposures in monkeys at the NOAEL. The predicted C_(max)of 223 ng/mL in the human with severe renal impairment is 2.8-3.5 timesless than the C_(max) in monkeys at the NOAEL of 2 mg/kg/day. Exposure(AUC_(0-inf)) in monkeys at 2 mg/kg/day is approximately half thepredicted daily exposure in severe renal impairment, and approximatelyequal to that in moderate renal impairment. At a dose of 10 mg/kg/day inmonkeys, the exposure exceeds the predicted daily exposure in severerenal impairment by 1.5-3.2 times, and exceeds that predicted formoderate renal impairment by 3.0-6.3 times (Table 10).

TABLE 8 Modeled and Measured PK Parameters for Lorcaserin, M1, and M5Following 10 mg BID Dosing Lorcaserin^(a) M1^(b) M5^(c) Renal t_(1/2)C_(max) AUC_(24 hr) t_(1/2) C_(max) AUC_(24 hr) t_(1/2) C_(max)AUC_(24 hr) Function Dose Regimen Duration (hr) (ng/mL) (hr · ng/mL)(hr) (ng/mL) (hr · ng/mL) (hr) (ng/mL) (hr · ng/mL) Normal QD AuthenticDay 1 11.0 37.0 482 36.2 33.6 1270 12.2 70.5 345 BID Simulation^(d)Steady State 8.28 55.8 942 30.0 130 2790 6.11 77.3 765 Mild QD AuthenticDay 1 13.0 36.3 623 45.5 43.5 1940 10.7 62.4 482 BID Simulation SteadyState 12.0 64.1 1270 34.6 207 4620 5.41 78.1 1090 Moderate QD AuthenticDay 1 15.9 26.2 515 70.8 34.1 2240 15.4 96.4 944 BID Simulation SteadyState 11.5 49.5 935 109 414 9670 9.83 141 2150 Severe QD Authentic Day 115.0 26.4 469 220 103 7850 14.9 153 2290 BID Simulation Steady State12.8 40.9 835 99.2 1090 25500 11.0 223 4260 ESRD QD Authentic Day 1 43.827.2 618 UD 67.6 3650 25.7 300 9530 BID Simulation Steady State 24.887.6 1860 UD — — 22.9 936 20100 Abbreviations: QD = once a day, BID =twice a day, ESRD = end stage renal disease ^(d)10 mg QD Authenticlorcaserin mean values were determined from the individual plasmaconcentration versus time profiles: source: APD356-016 CSR: Tables14.2.1.2.1, 14.2.1.2.2, 14.2.1.2.3, 14.2.1.2.4, 14.2.1.2.5 e 10 mg QDAuthentic M1 mean values were determined from the individual plasmaconcentration versus time profiles: source: APD356-016 CSR: Tables14.2.2.2.1, 14.2.2.2.2, 14.2.2.2.3, 14.2.2.2.4, 14.2.2.2.5 f 10 mg QDAuthentic M5 mean values were determined from the individual plasmaconcentration versus time profiles: source: APD356-016 CSR: Tables14.2.3.2.1, 14.2.3.2.2, 14.2.3.2.3, 14.2.3.2.4, 14.2.3.2.5 g 10 mglorcaserin BID Simulation steady state values were determined from Day 1mean plasma concentration versus time profiles: simulation parametersare described in PDR-09-151

TABLE 9 M1 Pharmacokinetics after Oral Administration of Lorcaserin:Preclinical Toxicology C_(max) AUC_(last) AUC_(0-inf) Dose t_(max) (hr)(μg/mL) (μg · hr/mL) (μg · hr/mL) Species Duration (mg/kg/day) M F M F MF M F Mice 52 wk  5 0.5 0.5 10.8 14.4   59.7   74.4   61.2   75.2 25 0.50.5 25.4 39.8 223 217 UD 221 50 0.5 0.5 42.7 49.1 308 345 319 356 Rats52 wk 10 1.0 1.0 15.4 16.3 170 193 175 200 30 1.0 4.0 23.9 31.7 319 412338 443 100  0.5 2.0 36.0 63.7 633 1050  927 1480  Monkeys 52 wk   2^(g)3.0 ± 1.2 1.5 ± 0.6 5.01 ± 2.16 4.58 ± 1.70 56.4 ± 14.3 39.3 ± 1.8  61.6± 15.4 40.9 ± 1.6 10 3.3 ± 1.5 2.5 ± 1.0 22.0 ± 7.6  27.5 ± 6.6  276 ±74  269 ± 40 312 ± 79 307 ± 66 50 4.7 ± 1.6 5.2 ± 2.4 62.3 ± 14.1 56.3 ±13.4 904 ± 228  771 ± 182 1060 ± 313  877 ± 221 125  3.7 ± 2.3 3.5 ± 2.5106 ± 31  115 ± 24  1460 ± 269  1580 ± 501 2020 ± 856 1910 ± 865 UD,undefined terminal phase Source: 2.6.4, Pharmacokinetics WrittenSummary, Table 16

M5 is pharmacologically inactive at all receptors, transporters and ionchannels tested to date. The highest individual overall exposure in asubject not on hemodialysis was observed in subject 3140-010 (creatinineclearance 9.9 mL/min), with AUC_(0-inf) of 6.48 μg·hr/mL. The highestexposure overall was observed in a subject with ESRD on hemodialysis,whose AUC_(0-inf) was 20.8 μg·hr/mL. The highest observed C_(max) in theclinical study was 520 ng/mL in a subject with ESRD (subject #3140-505).Consistent with the absence of detectable M5 pharmacological activity,neither of these subjects reported any adverse events. Similarly, M1 ispharmacologically inactive when tested at a concentration of 10 μMagainst a panel of receptors, ion channels and transporters.

TABLE 10 M5 Pharmacokinetics after Oral Administration of Lorcaserin:Preclinical Toxicology C_(max) AUC_(last) AUC_(0-inf) Dose (mg/ t_(max)(hr) (μg/mL) (μg · hr/mL) (μg · hr/mL) Species Duration kg/day) M F M FM F M F Mice 52 weeks 5 0.5 0.5 0.0983 0.100 0.134 0.184 0.178 0.201 250.5 0.5 0.590 0.431 1.84 1.21 UD UD 50 0.5 0.5 1.00 0.824 3.42 3.23 3.473.26 Rats 52 weeks 10 1.0 0.5 0.178 0.0538 0.550 0.273 0.602 0.349 300.5 1.0 0.559 0.337 3.07 1.62 3.1 1.96 100 0.5 2.0 2.03 1.20 14.9 11.116.5 12.8 Monkeys 52 weeks 2 0.8 ± 0.3 0.5 ± 0.0 0.635 ± 0.310 0.771 ±0.104 1.82 ± 0.57 1.76 ± 0.83 2.38 ± 0.29 2.13 ± 0.82 10 1.8 ± 0.5 1.0 ±0.7 2.48 ± 1.14  1.67 ± 0..63 12.5 ± 6.1  6.14 ± 1.71 13.6 ± 5.0  6.52 ±1.52 50 2.3 ± 1.9 3.2 ± 1.8 7.04 ± 2.05 3.60 ± 0.62 69.0 ± 25.8 38.7 ±12.7 71.4 ± 26.6 40.4 ± 13.4 125 2.2 ± 1.9 2.7 ± 2.0 15.8 ± 3.7  19.7 ±13.5 170 ± 64  134 ± 78  182 ± 77  140 ± 78  UD, undefined terminalphase Source: 2.6.4, Pharmacokinetics Written Summary, Table 17

Given the predicted level of M1 and M5 in patients with severe renalimpairment (creatinine clearance≦30 mL/min), including end stage renaldisease on hemodialysis, lorcascrin should not be used in these patientspending further study. Lorcaserin should be used with caution inpatients with moderate renal impairment, defined as creatinine clearance30-50 mL/min.

Example 6

Adverse Events (AEs) in the Renal Impairment Clinical Study

The incidence of adverse events was not related to severity of renalimpairment. Events considered possibly or probably related to lorcaserinincluded 1 event each of abdominal pain (moderate group), diarrhea(moderate group), dyspepsia (mild group), stomach discomfort (mildgroup), and worsening renal impairment (moderate group). Two events ofdizziness (I in severe group, one in ESRD group) and 3 events ofheadache (2 normal, 1 moderate group) were considered possibly/probablyrelated to study drug. A summary of the Treatment Emergent AdverseEvents in the APD356-016 study by renal impairment groups andrelationship to study drug are listed in Table 11.

TABLE 11 Summary of Treatment Emergent AEs in Clinical Study APD356-016by Renal Impairment Group Normal Mild Moderate Severe End Stage (N = 8)(N = 8) (N = 8) (N = 8) (N = 8) Number (%) of Subjects 4 (50.0%) 2(25.0%) 5 (62.5%) 3 (37.5%) 1 (12.5%) Reporting AEs Number of AEsReported^(a) 4 3 9 4 1 Number (%) of Subjects Reporting AEs By MaximumIntensity^(b) Mild 4 (50.0%) 2 (25.0%) 4 (50.0%) 3 (37.5%) 1 (12.5%)Moderate 0 (0.0%) 0 (0.0%) 1 (12.5%) 0 (0.0%) 0 (0.0%) Severe 0 (0.0%) 0(0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Number (%) of Subjects Reporting AEsBy Most Direct Relationship to Study Treatment^(b) Probable 1 (12.5%) 1(12.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Possible 1 (12.5%) 1 (12.5%) 3(37.5%) 1 (12.5%) 0 (0.0%) Unlikely 2 (25.0%) 0 (0.0%) 1 (12.5%) 2(25.0%) 0 (0.0%) Not Related 0 (0.0%) 0 (0.0%) 1 (12.5%) 0 (0.0%) 1(12.5%) ^(a)In counting the number of adverse events reported, anadverse event was defined as an event with a unique subjectidentification number, System Organ Class and preferred term.^(b)Subjects reporting one or more adverse events are counted once atthe maximum intensity and most direct relationship of all adverseevents. Source: APD356-016 CSR, Table 14.3.1

No clear trends in vital signs, laboratory values, or ECG attributableto lorcaserin were noted in the renal impairment study.

Example 7

Analysis of Renal Impairment in Phase 2 and Pooled Phase 3 ClinicalTrials

No patient in the APD356-004 phase 2b study had a creatinine greaterthan 1.3 mg/dL at any time during the trial, and no patient in theAPD356-003 study had a creatinine higher than 1.5. Hence, the discussionof adverse events observed in patients with renal impairment isrestricted to the pooled phase 3 trials.

Few patients in the APD356-009 trial developed creatinine values aboveor creatinine clearance values below normal (Table 12). At study entry,no patient had creatinine clearance less than 30 mL/min, and only 4 (1randomized to lorcaserin, 3 to placebo) had values below 40 mL/min basedon ideal body weight. In the APD356-011 study, 2 patients (1 placebo, 1lorcaserin BID) had a creatinine clearance less than 30 mL/min (based onideal body weight) at randomization. Given the small number of patientswith moderate or greater renal impairment in the phase 3 studies, ameaningful evaluation of the relationship between adverse events andrenal impairment is not possible. Lorcaserin did not, however, appear toaffect renal function. Creatinine clearance at last measurement did notdiffer meaningfully among treatment groups (Table 12). Table 12. Summaryof Creatinine and Creatinine Clearance Outside Predefined Limits during52 Weeks in Pooled Phase 3 Studies

TABLE 12 Summary of Creatinine and Creatinine Clearance OutsidePredefined Limits during 52 Weeks in Pooled Phase 3 Studies LaboratoryLimits of Parameter Change Treatment Group n/N^(a) (%)Creatinine >Baseline Pooled Placebo 1572/2918 (53.9) or >ULN Lorcaserin10 mg 431/754 (57.2) QD Lorcaserin 10 mg 1589/2992 (53.1) BID Pooled AnyLorcaserin 2020/3746 (53.9) Dose Creatinine >1.5x Baseline PooledPlacebo 16/2918 (0.5) or >1.5x ULN Lorcaserin 10 mg 5/754 (0.7) QDLorcaserin 10 mg 15/2992 (0.5) BID Pooled Any Lorcaserin 20/3746 (0.5)Dose Creatinine >3x Baseline Pooled Placebo 2/2918 (<0.1) or >3x ULNLorcaserin 10 mg 0/754 (0.0) QD Lorcaserin 10 mg 1/2992 (<0.1) BIDPooled Any Lorcaserin 1/3746 (<0.1) Dose N Treatment Group Mean (SD)Creatinine 2918 Pooled Placebo 83.85 (20.143) Clearance 754 Lorcaserin10 mg 85.24 (20.812) at Baseline QD (Ideal Body 2992 Lorcaserin 10 mg83.96 (19.769) Weight) BID Pooled 3746 Any Lorcaserin 84.22 (19.987)Dose Mean (SEM) Change from N Treatment Group Baseline Creatinine 2918Pooled Placebo −0.28 (0.186) Clearance 754 Lorcaserin 10 mg −0.67(0.391) at Last QD Observation 2992 Lorcaserin 10 mg 0.47 (0.181) (IdealBody BID Pooled Weight) 3746 Any Lorcaserin 0.25 (0.165) DoseAbbreviations: BL = baseline; LLN = lower limit of normal; ULN = upperlimit of normal. Note: Ideal body weight is used for creatinineclearance calculation to avoid confounding effect of weight loss cNumber of patients with baseline and at least one post baseline tests.Source: Statistical Report for the Integrated Summary of Safety, TableS12.1, S13.1 and S14.0

Lorcaserin exposure was not meaningfully affected by renal impairment.Neither renal nor total lorcascrin clearance was correlated with renalfunction (creatinine clearance). Metabolites M1 and M5 were alsoevaluated. Of note, neither metabolite is active at serotonin receptorsor at a panel of more than 60 GPCRs, transporters and ion channels.Exposure of M1, indicated by AUC_(0-inf), was correlated with renalfunction. M5 is the major urinary metabolite of lorcaserin; accordingly,exposure (AUC_(0-inf)) was significantly correlated with renal function.Based on clinical findings and the current guidance provided by theFederal Drug Agency, no lorcaserin dose adjustment should be needed inpatients with mild or moderate renal impairment. Given the predictedlevel of M1 and M5 in patients with severe renal impairment (creatinineclearance≦30 mL/min), lorcaserin should be used with caution in patientswith moderate renal impairment (creatinine clearance 30-50 mL/min) andshould not be used in patients with severe renal impairment (creatinineclearance≦30 mL/min) or end stage renal disease requiring hemodialysis.

Example 8

Individual Variation in HSO3-APD356 Metabolite (M1) C_(max) in SevereRenal Impairment Group

The modeled steady state C_(max) for metabolite M1 is 1090 ng/mL—this isessentially an estimated mean value. As shown in Table 13, actual M1levels were variable, with C_(max) values ranging from about 25 to about540 ng/mL at 4 hours on day 1. Maximum individual C_(max) was more thanfive times the mean C_(max) for the subjects studied. Hence, one mightpredict that some individuals would reach level of more than 5000 ng/mL(5 μg/mL) at steady state. This is approximately the C_(max) in monkeysgiven a 2 mg/kg dose (the NOAEL dose, see Table 9 above). This providesno margin between anticipated exposures and exposures that may producetoxicity. The FDA expects a reasonable margin between anticipatedexposures and exposures that may produce toxicity. A reasonable margincan vary depending on the expected toxicity, but generally is an orderof magnitude (10 times), but can sometimes be less for mild toxicity.

TABLE 13 Summary of Plasma Concentration (ng/mL) of HSO3-APD356Metabolite over Time by Group: Severe Renal Impairment Not ReceivingDialysis Subject Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 ID Predose 0.5 h 1h 2 h 3 h 4 h 6 h 8 h 12 h 16 h 24 h 36 h 48 h 72 h 96 h 120 h 3140-0020.00 12.2 31.4 53.2 55.6 55.1 46.5 50.4 52.2 18.0 62.4 52.2 54.2 46.243.8 40.1 3140-010 0.00 0.00 4.30 13.3 20.9 25.4 26.1 25.8 25.4 28.031.6 30.6 33.3 30.2 32.3 28.6 3285-001 0.00 0.00 7.19 23.9 28.5 32.833.3 29.8 29.5 30.6 32.0 28.4 25.8 19.7 15.1 12.3 3285-003 0.00 0.002.43 12.9 25.2 30.3 28.5 25.8 28.2 25.4 27.1 27.8 26.7 21.2 19.1 18.53285-009 0.00 182 319 489 468 542 445 473 439 410 406 336 292 248 225212 3286-004 0.00 2.66 22.8 42.2 52.4 53.3 51.9 49.7 45.9 46.9 51.1 45.547.2 40.2 36.0 30.4 3286-007 9.00 8.54 18.0 25.1 26.5 28.2 32.2 27.827.2 28.1 33.0 40.4 34.3 33.0 30.2 26.3 3286-009 0.00 0.00 0.00 6.0817.6 28.6 29.8 29.2 27.3 27.5 31.9 30.6 31.0 27.9 28.5 25.2 N 8 8 8 8 88 8 8 8 8 8 8 8 8 8 8 Mean 1.13 25.7 50.6 83.2 86.8 99.5 86.7 88.9 84.376.8 84.4 73.9 68.1 58.3 53.8 49.2 SD 3.18 63.3 109.0 164.7 154.7 179.2145.1 155.5 143.6 134.9 130.5 106.3 91.0 77.2 69.8 66.3 Median 0.00 1.3312.6 24.5 27.5 31.6 32.8 29.5 28.9 28.1 32.5 35.5 33.8 31.6 31.3 27.5Min 0.00 0.00 0.00 6.08 17.6 25.4 26.1 25.8 25.4 18.0 27.1 27.8 25.819.7 15.1 12.3 Max 9.00 182 319 489 468 542 445 473 439 410 406 336 292248 225 212 CV (%) ^(a) 283 247 215 198 178 180 167 175 170 176 155 144134 132 130 135 ^(a) % CV = Standard Deviation/Mean * 100.

Example 9

Serum Creatinine and Cockcroft-Gault Equation Creatinine ClearanceValues for Individual Subjects

Two individuals have been noted above with significantly higher C_(max)values for either metabolite M1 or M5 (see Table 14). Subject number328-009 was grouped in the severe renal impairment group and had thehighest observed C_(max) levels for metabolite M1. Subject number3140-505 was on dialysis and grouped in the end stage renal diseasegroup. This subject had the highest observed C_(max) for metabolite M5.

TABLE 14 Individual Subject Data Cockcroft-Gault Creatinine Renal SerumClearance Subject Impairment Creatinine (mL/min) (IDEAL ID Number AgeGender Race Group (mg/dL) body weight) 3140-005 73 MALE White or 2 1.254.8 Caucasian 3285-004 71 MALE White or 2 1.2 56.3 Caucasian 3285-00278 MALE White or 2 0.9 57.9 Caucasian 3140-006 50 FEMALE Black or 2 158.1 African American 3286-003 50 FEMALE Black or 2 0.9 68 AfricanAmerican 3286-011 55 MALE Asian 2 1.1 70.9 3140-004 35 MALE Black or 21.2 74.7 African American 3285-005 59 FEMALE White or 2 0.7 76.5Caucasian 3285-008 68 MALE White or 3 1.9 30.9 Caucasian 3286-010 60MALE Black or 3 2.5 36.5 African American 3140-003 75 MALE White or 31.5 37 Caucasian 3286-008 73 FEMALE White or 3 1.1 37.7 Caucasian3285-011 72 MALE White or 3 1.5 38.1 Caucasian 3286-006 42 MALE Black or3 2.8 42 African American 3286-002 62 MALE White or 3 2 42.7 Caucasian3140-001 71 MALE White or 3 1.5 46.6 Caucasian 3140-010 62 MALE White or4 7.5 9.7 Caucasian 3286-007 52 MALE White or 4 3.6 20.5 Caucasian3285-003 42 MALE White or 4 3.7 22.3 Caucasian 3286-009 61 FEMALE Whiteor 4 2.5 24.2 Caucasian 3140-002 75 FEMALE White or 4 1.9 24.9 Caucasian3285-001 75 FEMALE White or 4 1.6 25.6 Caucasian 3286-004 36 MALE Blackor 4 3.3 26.7 African American 3285-009 50 MALE Black or 4 3.8 28African American 3140-501 44 MALE Black or 5 13.6 0 African American3140-502 49 MALE Black or 5 5.2 0 African American 3140-503 39 MALEBlack or 5 7.8 0 African American 3140-504 46 MALE Black or 5 8.7 0African American 3140-507 57 MALE Black or 5 10.6 0 African American3140-508 56 MALE Hispanic or 5 11.6 0 Latino 3140-505 44 MALE Black or 510.4 0 African American 3140-506 46 FEMALE Black or 5 11.4 0 AfricanAmerican 3286-001 41 MALE White or 1 1.1 90.5 Caucasian 3285-006 23FEMALE White or 1 0.8 92.1 Caucasian 3140-007 33 MALE Black or 1 1 95.1African American 3286-005 22 MALE Black or 1 1.1 103.5 African American3285-007 19 MALE Hispanic or 1 1.1 106.3 Latino 3285-010 45 MALE Blackor 1 0.9 113.9 African American 3140-008 21 MALE White or 1 1 114.9Caucasian 3140-009 25 MALE Hispanic or 1 0.9 125.5 Latino RenalImpairment Groups: Normal (1), Mild (2), Moderate (3), Severe (4), Endstage renal disease on dialysis (5).

Example 10

Use of Lorcaserin in Renal Impairment Population

The disposition of lorcaserin was studied in patients with varyingdegrees of renal function. Impaired renal function has little or noinfluence on lorcaserin pharmacokinetics. However, exposure ofmetabolites M1 (lorcaserin sulfamate) and M5 (N-carbamoyl glucuronidelorcaserin) is significantly correlated with creatinine clearance(CLcr). Exposure (Geometric Mean Ratio for AUC_(inf)) of metabolite M1was increased in patients with impaired renal function by 1.6-fold inmild (CLcr=51-80 mL/min), 2.3-fold in moderate (CLcr=31-50 mL/min) and16.7-fold in severe renal impairment (CLcr=5-30 mL/min) compared tonormal subjects (CLcr>80 mL/min). Exposure (Geometric Mean Ratio forAUC_(inf)) of metabolite M5 was increased in patients with impairedrenal function by 1.2-fold in mild (CLcr=51-80 mL/min), 2.3-fold inmoderate (CLcr=31-50 mL/min) and 5.2-fold in severe renal impairment(CLcr=5-30 mL/min) compared to normal subjects (CLcr>80 mL/min). Theterminal half-life of M1 is prolonged by 26%, 96%, and 508% in mild,moderate, and severe renal impairment, respectively. The terminalhalf-life of M5 is prolonged by 0%, 26%, and 22% in mild, moderate, andsevere renal impairment, respectively. The metabolites M1 and M5accumulate in patients with severely impaired renal function on chronicadministration. The pharmacologic response is not affected by renalfunction. Approximately 18% of metabolite M5 in the body was clearedfrom the body during a standard 4-hour hemodialysis procedure.Lorcaserin and M1 were not cleared by hemodialysis. Lorcaserin is notrecommended for patients with severe renal impairment (i.e., CLcr≦30mL/min).

Patients with severe renal impairment can be identified using the tablebelow—do not use lorcaserin if the serum creatinine exceeds thepatient-appropriate value in Table 15.

TABLE 15 Identification of individuals with severe renal impairmentApproximate Serum Creatine (mg/dL) Age Range Men Women 18-20 >4.9 >3.521-30 >4.5 >3.2 31-40 >4.1 >2.9 41-50 >3.7 >2.7 51-60 >3.3 >2.4 >60 >3.0>2.0

Example 11

Determination of NOAEL Doses

In the mouse, seizures occurred at single doses of 100 and 300 mg/kglorcaserin, and death followed single doses of 1000 and 2000 mg/kg. Inrepeat dose studies in mice, mortality occurred at doses ≧200 mg/kg. Adose of 250 mg/kg/day produced exposure multiples of 25 and 27 times(males and females) the exposure achieved in humans at a dose of 10 mgBID. At this dose, decreased red blood cell mass, increasedreticulocytosis, increased liver weight, centrilobular hepatocellularhypertrophy, increased extramedullary hematopoeisis, and thymic necrosisoccurred. The NOAEL in mice was 50 mg/kg/day, which produced exposuremultiples of 7.6 and 2.3 (males and females) times the exposure inhumans at 10 mg BID.

In rats, a single 1000 mg/kg dose caused death. In 10-day repeat dosestudies, no mortality was observed at doses ≦150 mg/kg/day. The highestdose tested in 28-day studies, 50 mg/kg/day, was associated withincreased serum lipids, centrilobular hepatocellular hypertrophy,splenic extramedullary hematopoiesis, increased pigmented macrophages,and reticulocytosis, and increased kidney weights, with minimal renaltubular epithelial hyperplasia in males only. A 13-week study and a6-month study gave similar findings except there was no renal tubularepithelial changes and increases in kidney weights were limited to the3-month study; the NOAEL was 5 mg/kg/day, which produced exposuremultiples of 1.2 and 2.8 (males and females) relative to human exposureat a dose of 10 mg BID. At the highest dose given for 6 months, 50mg/kg/day, some mortality was observed in addition to the previouslyobserved findings, except there were no increases in kidney weights orother renal findings; exposure multiples were 22 and 34 (males andfemales) times human exposure at a dose of 10 mg BID.

In cynomolgus monkeys, dose-limiting emesis occurred at 300 mg/kg singledose. In repeat

dose studies, the maximum tolerated dose was 100-125 mg/kg/day, and wasassociated with emesis, decreased activity, and penile extension. In a28-day repeat dose study, one male given 100 mg/kg/day experienced aseizure. Exposure multiples of 74 and 68 (males and females) relative tohuman exposure at 10 mg BID were reached at a dose of 100 mg/kg/day.Reduced weight gain and food consumption occurred in 28-day, 13-week and12-month studies at doses ≧10 mg/kg/day. Cholesterol, LDL and HDLdecreased at ≧10 mg/kg/day in the 12-month study. Focal tubularepithelial cell degeneration and/or regeneration were observed in thekidneys in 0/8, 1/8, 2/8, 3/8, and 6/8 animals given 0, 2, 10, 50, and125 mg/kg lorcaserin, respectively. Cystic ovarian follicles wereobserved in the ovaries of 0/4, 0/4, 1/4, 1/4, and 3/4 females given 0,2, 10, 50 or 125 mg/kg lorcaserin, respectively; the finding wasreversible. The NOAEL was considered to be 2 mg/kg/day.

In rats but not mice, modest increases in kidney weights were reportedat high dose (≧50 mg/kg) in the 10-day, 28-day and 3-month studies, butwere without microscopic correlate except in the 28-day study, in whichminimal renal tubular epithelial hypertrophy was reported in male rats.In the one year toxicology study in monkeys, minimal to moderate focaltubular epithelial degeneration and/or regeneration were observed. Thepotential clinical relevance of this finding was evaluated in two ways.First, two pathologists with expertise in human renal pathology (HelmutRennke, M.D. and Stephen Bonsib, M.D.) independently reviewed all monkeykidney slides from the 1-year study in a blinded manner. Both reportedthe findings to be mild and focal, clinically unimportant, without doserelationship, and more likely related to aging, infection, orinflammation than to study drug. Secondly, renal function was monitoredin clinical trials not only by measuring creatinine and BUN, but also byexamining urine sediment and by calculating creatinine clearance. Theurine sediment data are of limited value due to the preponderance of“dirty” urine specimens contaminated with epithelial cells and otherexternal debris. Neither BUN nor creatinine was affected by lorcaserin.Creatinine clearance, which was calculated using both actual body weightand the preferred ideal body weight method, was also not affected bylorcaserin use of up to 2 years.

Example 12

Toxicity Study in Monkeys

Lorcaserin doses of 0, 2, 10, 50, and 125 mg/kg in a 5 mL/kg dose volumewere administered by nasogastric intubation once daily for 12 months tocynomolgus monkeys (4 to 6/sex/group). Two animals/sex from the control,50 and 125 mg/kg groups were continued on study without further dosingfor an additional 4 weeks prior to termination. For the first 91 days ofthe study, dose solutions were prepared using anhydrous lorcaserin.Starting on Day 92 and continuing for the remainder of the study, dosesolutions were prepared using lorcascrin hemihydrate to match theintended commercial form. The theoretical presumption of bioequivalenceof the two forms was confirmed in a pharmacokinetic study, and bysimilar exposures on Day 91 and 92 in this study. Evaluations includedclinical signs, food consumption, BW, electrocardiograms, ophthalmicexams, and clinical pathology indices. Blood samples were collected forTK analysis on Day 1, Week 4, Day 91, Day 92, and Week 52. A fullnecropsy was conducted on all animals, and tissues were collected,preserved, processed, and examined microscopically. Additional sectionsof heart were collected to allow comprehensive evaluation of all heartvalves. Heart histopathologic evaluation included atria, ventricles,interventricular septum, both AV valves (mitral and tricuspid), and theaortic and pulmonic valves.

There were no lorcascrin-related deaths in this study; however, twoanimals died prior to study completion, both of apparent dosingintubation accidents. A seizure was observed in a single high dose male42 min after the first dose on Day 1. This animal continued treatment onDay 2 and no further seizures were observed throughout the duration ofthe study. A dose-dependent decrease in activity and hunched appearancewere noted in both sexes at doses ≧10 mg/kg. In addition, there was anincrease in the incidence of tremors (females only) and emesis in thehigh dose group and these did not occur during the recovery period. Adose-dependent decrease in food consumption was measured which resultedin decreased weight gain for some animals that was more pronounced infemales. Mild reticulocytosis without accompanying reductions in redcell mass were observed at the 125 mg/kg dose. A reduction in serumlipids (cholesterol, HDL, and LDL) was measured in both sexes treatedwith ≧10 mg/kg doses of lorcaserin. Reductions in total cholesterol andLDL occurred in some animals treated with 2 mg/kg as well. There was adose-independent reduction in the mean triglyceride concentration inboth sexes at ≧2 mg/kg. Mild increases in ALT occurred primarily infemales at all dose levels and in one control animal. White blood cellsin the urine of some females dosed at ≧50 mg/kg/day were thought to beassociated with renal tubular changes noted histologically in three outof five cases.

There were no lorcaserin-related gross findings. Histologic changes wereidentified in the kidneys, ovaries, and possibly in the liver. Changesin the kidney consisted of focal or multifocal tubular epithelial celldegeneration, regeneration, and cellular casts. Minimal to mild tubularepithelial degeneration was observed in 6 of 8 animals in the high dosegroup (125 mg/kg). Minimal to mild epithelial regeneration was observedin the renal cortex of 0/8, 1/8, 2/8, 3/8 and 6/8 animals given 0, 2,10, 50, and 125 mg/kg lorcaserin, respectively, and moderateregeneration was found in 1 additional high dose animal (7/8 withregeneration in the 125 mg/kg group). Cellular casts were observed in1/4 males at 50 mg/kg and 4/4 animals at 125 mg/kg. The histologic renalchanges attributed to lorcaserin were not associated with changes inserum chemistry or kidney function. A review of the renal findings wasconducted by two expert human renal pathologists, each of whomindependently read blinded slides and reached the same conclusion: theadministration of lorcaserin to monkeys for 12 months was not associatedwith drug-related renal pathology. In their opinions, renalhistopathologic findings were mild and focal, showed no relationship tostudy drug administration and were most consistent with aging,infection, or inflammation rather than lorcascrin effects. One of thesepathologists attributed the potential finding of regeneration to astaining artifact resulting in a bluish cytoplasmic discoloration.Cystic ovarian follicles were observed in the ovaries of 0/4, 0/4, 1/4,1/4, and 3/4 females given 0, 2, 10, 50 or 125 mg/kg lorcaserin,respectively. This change was reversible after a one month drug-freeinterval. Hepatic lipidosis had an uncertain relationship to lorcaserinadministration. It was generally of minimal to mild severity and wasobserved in 2/8, 4/8, 2/8, 3/8, and 4/8 animals given 0, 2, 10, 50 and250 mg/kg/day of lorcaserin, respectively. Alanine aminotransferaselevels between control and lorcaserin-treated monkeys were generallycomparable, indicating an uncertain relationship between increased ALTlevels and hepatic lipidosis. The lipidosis was not present in animalssacrificed after a one month drug-free interval. No changes wereidentified by the study pathologist or the peer review pathologist inthe heart, heart valves, pulmonary vessels or lungs of animals givenlorcaserin compared to controls.

Lorcaserin plasma exposure on Day 1 in male and female monkeys was doselinear from 2 to 125 mg/kg. Plasma exposure of M1 was less than doseproportional while exposure for M5 was more than dose proportional forboth sexes. Lorcaserin, M1, and M5 plasma exposures did not vary withthe change in lorcaserin salt form (i.e., anhydrous vs. hemihydrate).Repeat dosing of lorcaserin over 358 days resulted in modest increases(1.0 to 1.8-fold) in plasma exposure compared to a single dose,independent of gender for doses of 2 and 50 mg/kg/day. At the 125mg/kg/day dose, plasma exposure marginally decreased (˜10% to ˜40%) fromDay 1 to Day 358 in both male and female monkeys. Lorcaserin sulfamate(M1) and M5 were detected in the plasma at the first time pointcollected at 0.5 h, indicating that both were rapidly formed after oraladministration of lorcaserin. After single or multiple doses oflorcaserin, both M1 and M5 exposure was greater than that of the parentcompound, ranging from 20 to 160-fold higher for M1 and up to 3-foldhigher for M5 than the concomitant lorcaserin exposure. Study findingswere consistent with previous studies conducted in monkeys. As inprevious studies, no differences were observed between the heart valvesor lungs of controls and lorcaserin-treated animals. A NOAEL of 2 mg/kgwas determined by the conducting laboratory. The kidney findingpotentially related to lorcaserin at the NOAEL, i.e., a single focus ofminimal tubular regeneration in 1/8 animals, was not deemed adverse.

Renal Findings

In monkeys kidney changes were only observed in the 52-week study (2,10, 50, and 125 mg/kg/day). Changes in the kidney consisted of focaltubular epithelial cell degeneration, regeneration, and cellular casts.Minimal to mild tubular epithelial degeneration was observed in 6 of 8animals in the high dose group (125 mg/kg). Minimal to mild epithelialregeneration was observed in the renal cortex of 0/8, 1/8, 2/8, 3/8 and6/8 animals given 0, 2, 10, 50, and 125 mg/kg lorcaserin, respectively.At the high dose, moderate epithelial regeneration was observed in 1/4females. Cellular casts were observed in 1/4 males at 50 mg/kg and 1/4males and 2/4 females at 125 mg/kg. These findings were not observed inprevious monkey studies, and no similar kidney findings occurred inrodents. Renal findings were determined to be unrelated to lorcaserintreatment by two independent human renal pathologists after reviewingblinded slide sets. In their independent opinions, the findings were notdose related and were consistent with age and focal inflammation orinfection. One pathologist attributed the findings of regeneration to astaining artifact, resulting in a bluish cytoplasmic discoloration. Iftubular renal epithelial regeneration were artifactual, renal findingsof the conducting laboratory would be limited to the high dose. At 2,10, 50, and 125 mg/kg, the margins were 1.0 and 0.6, 8 and 5, 44 and 31,and 51 and 51 times human exposure at the MRD for males and females,respectively. Renal findings in rodents and monkeys were of uncertainrelationship to lorcaserin. Substantial margins over human exposureexist for all renal finding in rodents, and in monkeys according to twoexpert human renal pathologists. Even assuming the renal findings inmonkeys are drug related, the principal findings were focal ormultifocal, minimal to mild (1 instance of moderate regeneration at thehigh dose) renal tubular epithelial regeneration and degeneration thatwould have had to have been much more severe and diffuse to be ofclinical relevance. Based upon adverse events, clinical chemistry andurinalyses in an extensive phase 2 and phase 3 program, there is noevidence of a lorcaserin effect on the kidney in humans.

Example 13

Physical Properties of Compound 1 Hydrochloride Hemihydrate Form III

Compound 1 Hydrochloride Salt Hemihydrate

The physical properties of Form III of Compound 1 hydrochloride salthemihydrate are summarized in Table 16 below.

TABLE 16 Compound 1 Hydrochloride Salt Hemihydrate, Form III PXRD FIG.6: Peaks at 13.7°, 14.9°, 15.4°, 15.8°, 16.7°, 18.9°2θ DSC FIG. 7: 95°C. (dehydration); 200° C. (melt) TGA FIG. 8: 3.7% water loss DMS FIG. 9:non-hygroscopic

Compound 1 hydrochloride salt hemihydrate, Form III displays adehydration feature calculated as a 3.7% weight loss which is consistentwith the theoretical weight loss of 3.7% for a hemihydrate. Analysis byDSC further confirms the TGA results, where Compound 1 hydrochloridesalt hemihydrate, Form III shows a dehydration event at about 95° C. anda melting/decomposition endotherm at about 200-201° C.

DVS data shows that Compound 1 hydrochloride salt hemihydrate, Form IIIis substantially non-hygroscopic, adsorbing less than 0.5 wt % water at90% RH and the XRPD pattern showed no change in crystalline form afterthe DVS cycle.

Certain X-ray powder diffraction peaks for Compound 1 hydrochloride salthemihydrate, Form III are shown in Table 17 below.

TABLE 17 Pos. (°2θ) 10.2 12.7 13.7 14.9 15.4 15.8 16.7 18.5 18.9 19.220.1 25.3 25.7 26.0 26.5 26.9 27.6 28.2 20.5 21.4 22.8 23.2 23.5 24.024.2 24.7 29.0 30.0 30.3 30.8 31.1 32.0 32.3 32.7 33.3 33.8 35.8

Form III of Compound 1 hydrochloride salt hemihydrate can be prepared asdescribed in Example 14.

Example 14 Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideHemihydrate, Form III Method 1 Step A: Preparation of8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

2-Chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride (about 460kg, 1.71 kmol, 1.00 eq.), aluminum chloride (about 336 kg, 2.52 kmol,1.47 eq.), and 1,2-dichlorobenzene (about 1321 kg) are charged to avessel vented to a caustic scrubber. The mixture is then stirred andheated at about 126° C. under nitrogen for about 16 h. The resultingFriedel-Crafts reaction mixture is then cooled. Silica gel and purifiedwater (about 736 kg) are charged to a second vessel. The cooledFriedel-Crafts reaction mixture is then added to the aqueous silica gelslurry stirred and cooled in the second vessel. The stirred quenchmixture is filtered at about 55° C., and the silica gel filter cake iswashed with purified water (about 368 kg). Optionally, some or all ofthis purified water is used to rinse the quench vessel into the filter.

The mother and wash liquor filtrates are combined in a vessel and arecooled with stirring to about 22° C. Stirring is then stopped, and uponsettling, three phases separate. The brown, lowest phase consists mostlyof 1,2-dichlorobenzene and is drained. The lower of the remaining twophases, which is the middle phase of the original three-phase mixture,contains most of the product. The topmost phase is a turbid water phasecontaining a smaller amount of the product. These upper two phases arepartitioned between cyclohexane (about 506 kg) and enough aqueous sodiumhydroxide solution, approx. 30 wt %, to achieve an aqueous phase pH ofat least 12. The cyclohexane phase is washed with water (at least 300kg) at about 57° C. and then evaporated at reduced pressure to providecrude 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil.

Step B: Preparation of(R)-s-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Hemitartrate

Acetone (about 848 kg) is added to the crude8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine prepared in StepA. The vessel contents are stirred and heated to about 45° C. To theresulting solution is added a solution of L-(+)-tartaric acid (about57.0 kg, 380 mol, 0.222 eq.) in purified water (about 98.0 kg) while thestirred vessel contents are maintained at about 45° C. Stirring iscontinued for about 20 min.(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartratesalt seed crystals are then optionally added to initiate nucleation.Stirring is continued, and more acetone is added. The resultingsuspension is then cooled to about 2° C. The resulting precipitate iscollected by centrifugation and washed with acetone (about 440 kg), aportion of which is optionally used to rinse the crystallization vesselinto the centrifuge. The washed solid is discharged from the centrifuge,mixed with acetone (about 874 kg) and the mixture is stirred and heatedto reflux. While reflux is maintained, purified water (at least 329 kg)is added until complete dissolution is achieved at reflux. The resultingmixture is stirred at reflux and then cooled to about 2° C. over about2.5 hours. The resulting precipitate is collected by centrifugation andwashed with acetone (about 184 kg), a portion of which is optionallyused to rinse the crystallization vessel into the centrifuge. The washedsolid is discharged from the centrifuge and dried at elevatedtemperature under reduced pressure to provide(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartrate.The yield range is 100 kg to 158 kg.

Step C: Preparation of(R)-4-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideHemihydrate

Purified water (about 740 kg) is added to a stirred mixture of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartratefrom Step B (about 247 kg after correction for assay, 912 mol, 1.00eq.), potassium carbonate (about 151 kg, 1093 mol, 1.20 eq.), and ethylacetate (about 663 kg). The mixture is maintained at about 15° C. duringthe addition, after which it is stirred and then allowed to settle. Thelower (aqueous) phase is drained to waste disposal. Purified water(about 740 kg) is added to the upper (organic) phase, and the resultingmixture is stirred at about 22° C. and then allowed to settle. The lower(aqueous) phase is drained to waste disposal.

Solvent is removed from the upper (organic) phase by vacuum distillationat about 40° C. to provide(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as thedistillation residue. Ethyl acetate (about 1050 kg) is added, and themixture is stirred to achieve dissolution. If the water content of theresulting solution is found by Karl Fischer analysis to exceed 1.51 wt%, the procedure of this paragraph is repeated.

Through a polishing filter into a crystallization vessel is addedpurified water in the approximate amount calculated to provide a waterconcentration of 1.0 wt % in the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine solution afterthe final ethyl acetate dilution. The solution is then filtered throughthe same polishing filter into the crystallization vessel. The vessel inwhich the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hadbeen prepared is rinsed with additional fresh ethyl acetate (about 644kg), and the rinse is filtered through the same polishing filter intothe crystallization vessel.

The water content of the solution in the crystallization vessel isdetermined by Karl Fischer analysis. If the water content is about 0.8wt % to about 1.2 wt % (0.5 wt % to 1.5 wt % non-critical range), thenprocessing resumes at the beginning of the next paragraph. If the watercontent is too low, additional purified water is added through thepolishing filter. If the water content is too high, then solvent isremoved by vacuum distillation, purified water (about 18 kg) is addedthrough the polishing filter, and ethyl acetate (about 1800 kg) is addedthrough the polishing filter. In either case, the resulting solution istested for water content.

As the contents of the crystallization vessel are stirred, hydrogenchloride gas (about 3.3 kg, 91 mol, 0.10 eq.) is added to the vesselhead space. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride hemihydrate seed crystals are then added to initiatenucleation. Additional hydrogen chloride gas is then added to the vesselhead space until the pH of the reaction mixture drops to and remains atabout 5 or less. The precipitated product is collected by centrifugationand washed with filtered ethyl acetate (about 552 kg). The precipitateis dried under reduced pressure to provide the title compound. The yieldrange is 184 kg to 217 kg, which is 84% to 99% of theoreticaluncorrected for seed charge and 83% to 98%, of theoretical corrected forseed charge.

Method 2 Step A: Preparation of8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

1,2-Dichlorobenzene (about 1522 kg),2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride (about 530kg, 1.97 kmol, 1.00 eq.), and aluminum chloride (about 387 kg, 2.90kmol, 1.47 eq.) are charged to a vessel vented to a caustic scrubber.The mixture is then stirred and heated at about 126° C. under nitrogenfor about 16 h. The resulting Friedel-Crafts reaction mixture is thencooled. Purified or potable water (about 1060 kg) and silica gel arecharged to a second vessel. The cooled Friedel-Crafts reaction mixtureis then added to the aqueous silica gel slurry stirred and cooled in thesecond vessel. The stirred quench mixture is filtered at about 58° C.,and the silica gel filter cake is washed with purified or potable water(about 212 kg). Optionally, some or all of this water may be used torinse the quench vessel into the filter. The mother and wash liquorfiltrates are combined in a vessel and are cooled with stirring to about22° C. Stirring is then stopped, and upon settling, three phasesseparate. The brown lowest phase consists mostly of 1,2-dichlorobenzeneand is drained to solvent regeneration. The lower of the remaining twophases, which is the middle phase of the original three-phase mixture,contains most of the product. The topmost phase is a turbid water phasecontaining a smaller amount of the product. These upper two phases arepartitioned between cyclohexane (about 583 kg) and enough aqueous sodiumhydroxide solution, approx. 30 wt %, to achieve an aqueous phase pH ofat least about 13. The cyclohexane phase is washed with purified orpotable water (about 1272 kg) at about 57° C. and then distilled atreduced pressure to remove solvent and provide crude title compound, anoil, as the distillation residue.

Step B: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Hemitartrate

Acetone (about 977 kg) is added to the crude8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine prepared in StepA. The vessel contents are stirred and heated to about 45° C. To theresulting solution is added a solution of L-(+)-tartaric acid (about 66kg, 440 mol, 0.223 eq.) in purified or potable water (about 113 kg)while the stirred vessel contents are maintained at about 45° C. Abouthalf way through the tartaric acid addition,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartrateseed crystals are added to the solution to achieve cloudiness and toinitiate nucleation. Stirring is continued, and more acetone is added.The resulting suspension is then cooled to about 2° C. The resultingprecipitate is collected by centrifugation and washed with acetone(about 508 kg), a portion of which is optionally used to rinse thecrystallization vessel into the centrifuge. The washed solid is mixedwith acetone (about (1007 kg) and the mixture is stirred and heated toreflux. While reflux is maintained, purified or potable water (at leastabout 392 kg) is added until complete dissolution is achieved at reflux.The resulting mixture is stirred at reflux and then cooled to about 2°C. over about 2.5 h. The resulting precipitate is collected bycentrifugation and washed with acetone (about 212 kg), a portion ofwhich is optionally used to rinse the crystallization vessel into thecentrifuge. The washed solid is discharged from the centrifuge and driedat elevated temperature under reduced pressure to provide the titlecompound.

Step C: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideHemihydrate

Purified water (about 779 kg) is combined with(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartratefrom Step B (about 260 kg after correction for assay, 960 mol, 1.00eq.), potassium carbonate (about 159 kg, 1150 mol, 1.20 eq.), and ethylacetate (about 698 kg) with stirring at about 15 TC. The resultingmixture is stirred and then allowed to settle. The lower (aqueous) phaseis drained to waste disposal. Purified water (about 779 kg) is added tothe upper (organic) phase, and the resulting mixture is stirred at about22° C. and then allowed to settle. The lower (aqueous) phase is drainedto waste disposal.

Solvent is removed from the upper (organic) phase by vacuum distillationwith the jacket temperature increasing to about 60° C.(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, an oil, isobtained as the distillation residue. Ethyl acetate (about 1105 kg) isadded, and the mixture is stirred to achieve dissolution. If the watercontent of the resulting solution is found by Karl Fischer analysis toexceed 1.51 wt %, the procedure of this paragraph is repeated.

The solution in is then filtered through a polishing filter into acrystallization vessel. The vessel in which the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine had beenprepared is then rinsed with additional ethyl acetate (about 122 kg)through the same polishing filter into the crystallization vessel. Tothe crystallization vessel is then added purified water in theapproximate amount calculated to provide a water concentration of 1.0 wt% in the solution after the final ethyl acetate dilution. Ethyl acetate(about 556 kg) is then added to the crystallization vessel, and theresulting mixture is stirred. The water content of the solution in thecrystallization vessel is determined by Karl Fischer analysis. If thewater content is about 0.8 wt % to about 1.2 wt % (0.5 wt % to 1.5 wt %qualified range), then processing resumes at the beginning of the nextparagraph. If the water content is too low, additional purified water isadded. If the water content is too high, then solvent is removed byvacuum distillation, and purified water and ethyl acetate are added. Ineither case, the resulting solution is retested for water content.

As the contents of the crystallization vessel are stirred, hydrogenchloride gas (about 3.5 kg, 96 mol, 0.10 eq.) is added to the vesselhead space. (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride hemihydrate seed crystals are then added to initiatenucleation. Additional hydrogen chloride gas is then added to the vesselhead space until the pH of the reaction mixture drops to and remains atabout 3 or less. The precipitated product is collected by centrifugationand washed with ethyl acetate (about 580 kg) to provide the titlecompound (about 221 kg), which is dried in a tray or tumble dryer (suchas a double cone dryer) under reduced pressure at a jacket temperatureof about 26° C.

Method 3 Step A: Preparation of8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a reactor equipped with overhead agitation, jacket temperaturecontrol, a nitrogen inlet, and a caustic scrubber vent were charged, inthe specified order, 2-chloro-N-(4-chlorophenethyl)propan-1-aminehydrochloride (1.00 kg, 3.72 mol), aluminum chloride (0.745 kg, 5.58mol), and 1,2-dichlorobenzene (2.88 kg). The stirred reactor contentswere heated to 125-130° C., and stirring was continued at thattemperature for 14-18 h. At 60-70° C., a dark colored solution wasobtained. After reaction completion (<1.0% starting material by HPLCpeak area) had been verified, the stirred reactor contents were cooledto 30-35° C. To a second reactor vented to a caustic scrubber wascharged purified water (1.60 L) and silica gel (0.160 kg). TheFriedel-Crafts reaction mixture was transferred from the first reactorto the second reactor sufficiently slowly to maintain the stirredcontents of the second reactor at <60° C. After the transfer iscompleted, the next step may be executed without any hold period. Thesilica gel was filtered on a medium to coarse filter element at 55-60°C., and the filtered solids were subsequently washed with purified water(800 mL) preheated to 50-60° C. The combined mother and wash liquorfiltrates were cooled to 20-25° C. with vigorous agitation. Then thestirring was stopped, and the phases were allowed to separate at 20-25°C. (Process volume peaked at this point at 5.68 L). Three phasesseparated after 1-2 hours of standing. The lowest layer was drained towaste disposal. This dark layer consisted mostly of 1,2-dichlorobenzene(1.64 kg, 1.33 L) at pH 3-4. About 1% of the product was lost to thislayer. The remaining two phases were allowed to stand without agitationfor another 2-4 h. The lower layer was drained and saved (Layer A). Thislight colored phase (2.64 kg, 2.00 L, pH 2-3) contained ˜90%8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine. The upper layer(2.24 kg of a turbid water phase at pH 0-1) contains ˜1-4%8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine and remained in thereactor for back-extraction. The reactor was charged with cyclohexane(1.10 kg) and then 30% aqueous NaOH (2.44 kg, 18.3 mol). The resultingmixture (5.60 L) was stirred vigorously for 30 min at room temperature.The stirring was stopped, and the phases were allowed to separate for25-40 min. If the pH of the lower (aqueous) phase was ≧13, it wasdrained to waste disposal. Otherwise, more 30% aqueous NaOH was added,and this extraction was repeated. At pH 14, the aqueous phase contains<0.1% 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine free base. Theremaining upper (organic) phase from the reactor was drained and saved(Layer B). The reactor was rinsed with purified water and followed by asuitable organic solvent to remove residual salts. The lower,light-colored product phase (the middle of the original three phases,Layer A) and the upper phase (organic, Layer B) were returned to thereactor. To the stirred reactor contents was added 30% aqueous NaOH(1.60 kg, 12.0 mol). The reactor contents were stirred vigorously for0.5 hours. The stirring was discontinued and the phases were allowed toseparate over 15-30 minutes. The lower (aqueous) layer was drained towaste disposal. To the upper (organic) phase remaining in the reactorwas added purified water (2.40 kg). The reactor contents were stirredvigorously at 60-65° C. for 0.5 h. The stirring was discontinued, andthe phases were allowed to separate at 60-65° C. over 1.5-2 h. The lower(aqueous) layer was drained to waste disposal. With a reactor jackettemperature of 55-60° C., solvent from the upper (organic) layer wasremoved by vacuum distillation at pressures starting at 115-152 torr andfalling to 40 torr. The crude product,8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free base,was obtained as a yellow to brown oil distillation residue.

Step B: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Hemitartrate

The distillation residue from Step A (crude8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine as the free base)was dissolved in acetone (0.400 kg). The resulting solution was drainedand weighed to assay the8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine content by HPLC.Results of the assay were used to calculate charges of acetone,L-tartaric acid, and water. The quantities indicated below are typicalfor achievement of the target8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzazepine:acetone:L-tartaricacid:water mole ratio of 1.00:9.6:0.25:3.6 prior to addition of seedcrystals. More acetone (1.415 kg) was added to the reactor and thestirred reactor contents were heated to 47-52° C. To the resultingsolution was added a solution of L-tartaric acid (0.1223 kg, 0.815 mol)in purified water (0.211 kg) at a steady rate over 5-15 min. A thinsuspension formed during the addition but then redissolved when themixture temperature was reestablished at 50° C. Hemitartrate seedcrystals (0.80 g) were added to the 50° C. solution to achievecloudiness and to initiate nucleation. Nucleation was allowed tocontinue for 2-3 h with agitation at 47-52° C. Acetone (0.473 kg) wasadded to the reactor while the stirred reactor contents were maintainedat 50° C. The resulting suspension was cooled to 0-5° C. slowly over 3-5h. Stirring was continued at 0° C. for another 1-3 h. The resultingwhite precipitate was collected on a medium-to-fine filter element andthen washed with a mixture of acetone (0.900 kg) and purified water(0.054 kg). The enantiomeric excess (ee) of the wet cake was determined.

If the ee was <98%, the wet cake was transferred back into the reactorand reslurried in a mixture of acetone (1.90 kg) and purified water(0.400 kg) at 55-60° C. for 0.5-1 h. If dissolution had not beenachieved after one h, then water (approximately 0.160 kg) was addeduntil a clear solution was achieved. The resulting mixture was thencooled to 0-5° C. slowly over 2-3 h. Stirring at 0° C. was continued foranother 3-5 h. The resulting white precipitate was collected on amedium-to-fine filter element and then washed with acetone (0.400 kg) at0-4° C.

The washed solid product (296 g wet) was dried at 60-65° C. under fullvacuum for 15-20 hours. The yield of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartrate,with about 99.7% ee and 7.5 wt. % water content, was 295 g (27.1% basedon racemic 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochlorideand corrected for product water content).

Step C: Preparation of(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HydrochlorideHemihydrate, Form III

To a reactor equipped with overhead agitation and a nitrogen inlet wascharged, in the specified order,(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemitartrate(1.00 kg containing 7.5 wt % water, 1.71 mol), potassium carbonate(0.508 kg, 3.68 moles), ethyl acetate (2.68 kg), and purified water(2.68 kg). The resulting mixture was stirred at 20-25° C. for 30-40 min,and then the phases were allowed to separate over 0.5-1 h. The lower(aqueous) phase was drained to waste disposal. Purified water (2.68 kg)was added to the reactor, and the resulting mixture was vigorouslystirred for 10-20 min. The phases were allowed to separate over 1-1.5 h.The lower (aqueous) phase was drained to waste disposal. With thereactor contents at a temperature of 40-45° C., the solvent was removedby vacuum distillation at pressures falling from 153 torr to 46 tort.The residue was cooled to 20-25 TC. Ethyl acetate (3.81 kg) was chargedto the reactor, and the distillation residue was dissolved withstirring. The water content of the resulting solution was verified byKarl Fischer analysis to be <0.8 wt. %. The solution was filteredthrough a polishing filter. The reactor was rinsed through the filterwith ethyl acetate (2.33 kg) previously verified by Karl Fischeranalysis to have <0.05 wt. % water content. Both the solution and rinsefiltrates were charged back into the reactor. Purified water (39.9 g)was added to the reactor. The stirred reactor contents were cooled to0-5° C., and then HCl gas (19.0 g, 0.521 mol) was added while thestirred reactor contents were maintained at 0-5° C.(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemihydrateseed crystals (1.33 g) were added to the stirred reactor contents toinitiate nucleation at 0-5° C. The remaining HCl gas (107.6 g, 2.95 mol)was charged to the reactor at a steady rate over at least 1.5-2 h whilethe stirred reactor contents were maintained at 0-5° C. The resultingsuspension was stirred at 0-5° C. for 2 h. The resulting whiteprecipitate was collected on a medium-to-fine filter element. Thereactor and then the filtered solid product were washed with ethylacetate (1.33 kg). The wet cake (ca. 867 g) was dried at full vacuum and33-37° C. for 20 h or until the cake temperature had been stable for 4hours, whichever occurred first. The resulting(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate (3.7 wt. % water content, 14.7% chloride content, <0.01%ROI, >99.6% ee, >99% HPLC purity, and <0.1% wrong isomer content) wasobtained in a yield of about 741 g (89.9%).

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of thedisclosure and are, therefore, considered within the scope of thedisclosure.

We claim:
 1. A method for weight management, comprising: administeringto an individual having moderate renal impairment and in need of saidweight management a therapeutically effective amount of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideor a hydrated form thereof, wherein said moderate renal impairment is acreatinine clearance from 31 mL/min to 50 mL/min in said individualdetermined by the Cockcroft-Gault equation using ideal body weight. 2.The method of claim 1, wherein the therapeutically effective amount isabout 10 mg of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride or a hydrated form thereof administered orally twicedaily.
 3. The method of claim 1, wherein the therapeutically effectiveamount is about 20 mg administered orally once daily.
 4. A method forweight management, comprising: administering to an individual havingmoderate renal impairment and in need of said weight management a doseof about 20 mg of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideor a hydrated form thereof, wherein said moderate renal impairment is acreatinine clearance from 31 mL/min to 50 mL/min in said individualdetermined by the Cockcroft-Gault equation using ideal body weight. 5.The method of claim 4, wherein the dose is administered as about 10 mgof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride or a hydrated form thereof orally twice daily.
 6. Themethod of claim 4, wherein the dose is administered orally once daily.